Influenza peptides and compositions

ABSTRACT

The present specification discloses recombinant nucleic acid constructs encoding an immunogenic multiepitope polypeptide comprising two or more polypeptides, recombinant nucleic acid constructs encoding at least two epitopes from two or more internal proteins of influenza virus, compositions comprising such recombinant nucleic acid constructs and methods of eliciting a T cell immune response against an influenza virus in a vertebrate using such recombinant nucleic acid constructs and compositions.

This is a continuation application and claims priority pursuant to 35U.S.C. § 120 to U.S. Non-Provisional patent application Ser. No.15/865,214, filed Jan. 8, 2018, a continuation application that claimspriority to U.S. Non-Provisional patent application Ser. No. 15/231,347,filed Aug. 8, 2016, now U.S. Pat. No. 9,889,191, a continuationapplication that claims priority to U.S. Non-Provisional patentapplication Ser. No. 13/906,232, filed May 30, 2013, now U.S. Pat. No.9,446,116, a continuation application that claims priority to U.S.Non-Provisional patent application Ser. No. 12/278,728, filed May 26,2009, now U.S. Pat. No. 8,475,802, a 35 U.S.C. § 371 National StageFiling of PCT/GB2007/000383, filed Feb. 5, 2007, an International PatentApplication that claims priority to GB 0613977.8, filed Jul. 13, 2006and GB 0602416.0, filed Feb. 7, 2006, each of which is herebyincorporated by reference in its entirety.

The invention concerns peptide sequences, compositions comprising thepeptide sequences, and in particular influenza vaccines comprising thesequences and the compositions, and uses of the sequences. The presentinvention is especially concerned with vaccines that are protectiveagainst a plurality of influenza virus strains, including existingviruses across different species (e.g. protective against both human andavian influenza) as well as future viruses that have mutated fromexisting viruses (such as a future mutated form of avian flu that isreadily transmissible from human to human, which could potentially giverise to an influenza pandemic).

The defense against disease is critical for the survival of all animals,and the defense mechanism employed for this purpose is the animal immunesystem. Understanding the immune system is therefore a key tounderstanding the development of new and more sophisticated treatmentsfor humans and animals alike.

The mechanism of operation of the immune system has been underinvestigation for many years. The system is composed of a number of celltypes and a variety of molecules, making it extremely complex. Evenafter many years of study, the full extent of the immune systemcomponents, and their interaction with each other, is imperfectlyunderstood.

Many years ago it was recognised that a person who recovers from aparticular disease may acquire some protection in future against thatdisease, but not against a disease which that person has not yetcontracted. This fundamental aspect of the immune system was interpretedat that time by considering that the immune system acquired a kind of‘memory’ against certain pathogens once exposure to such pathogens hadtaken place, that memory being specific to a certain disease.

Gradually, it became known that exposure to less harmful variants of apathogen could induce protection against more harmful variants (e.g.exposure to cowpox to protect against smallpox, or exposure to aninactivated anthrax to protect against live anthrax). Thus, the idea ofvaccination against a disease arose.

It is now known that the immune system has at least two divisions:innate immunity and adaptive immunity. The innate system is fullyfunctional before a pathogen enters the system, whilst the adaptivesystem is switched on after the pathogen enters the system. It thendevelops an attack specific to the pathogen. The innate system comprisesa number of components, including phagocytes such as macrophages, which(as the name suggests) ‘eat’ or engulf foreign bodies such as pathogens.

Typically, but not exclusively, the present invention is concerned withthe adaptive immune system, and unless specifically indicated otherwise,‘immune system’ in the present context refers to the adaptive immunesystem.

In order to understand more fully how the immune system functions, therole of its individual components must be carefully considered. Inrespect of the adaptive immune system, it is well known that immunityagainst pathogens is provided by the action of lymphocytes, whichconstitute the most common cell type in the immune system. There are twotypes of lymphocyte: the B lymphocyte and the T lymphocyte. These aregenerally termed B cells and T cells respectively.

B cells have the ability to develop into plasma cells, which manufactureantibodies. Antibodies are very important components of the animalimmune system. They are produced in response to some signature portionof the invading pathogen (an antigen of the pathogen—antigens here beingdefined as any foreign substance recognised by the immune system) andare usually specific to that pathogen. However, if two pathogens arevery similar, or at least contain the same antigen, then antibodiesproduced against one can nevertheless be effective against the other(they may ‘cross-react’). This explains why inoculation with cowpox mayprotect against smallpox. It is important to realise that the antibodies‘recognise’ only a small portion of the antigenic molecule of thepathogen rather than the pathogen as a whole. These portions are termedepitopes.

T cells do not possess or produce antibodies. Instead, they recognisefragments (i.e. epitopes) of the foreign antigen complexed with majorhistocompatibility complex (MHC) (or in the case of humans, humanleucocyte antigen (HLA)) via a specialised receptor known as TCR (T cellreceptor). T cells are themselves divisible into subsets which can haveeither a regulatory function or an effector function. The effector cellsare involved with ‘effecting’ the removal of foreign substances. Forexample, cytotoxic T cells (CTL) are effector cells that are able tokill infected cells, as well as other unwanted species such as tumourcells. Regulatory T cells, on the other hand, play a role in helpingeffector T and B cells to become more effective. Due to this function,these regulatory T cells are often termed ‘helper’ T cells. Otherregulatory T cells, termed ‘suppressor’ T cells, are thought to inhibitimmune responses, but these are less well understood. Regulatory T cellsmay also interact with components of the innate immune system to boosttheir activity.

In a normal healthy individual, the lymphocytes in the immune systemremain in an inactive ‘resting’ state until an immune response istriggered. When an immune response is required, the lymphocytes becomeactivated, proliferate and begin to carry out their designatedfunctions. For example, any resting T cell displaying on its surface aTCR that recognises an epitope of the invading pathogen complexed with aMHC molecule is activated, proliferates (this being termed clonalexpansion) and the resulting offspring start to actively carry out theirpredetermined effector functions required to combat the invadingorganisms.

When the immune response is completed, (i.e. the pathogens and/orinfected cells have been eliminated) the lymphocytes revert to a restingstate once again. This resting state is not, however, equivalent to theinitial inactive resting state. Activated, but resting lymphocytes, canbe rapidly recruited and induced to proliferate in response to aninfection by the same, or closely related, pathogen at a later time.

This ability of activated resting lymphocytes, to deliver a faster andmore powerful response following a second encounter with an invadingpathogen, effectively provides the immune system with ‘memory’. Theexploitation of the immune system's memory is the basis for alllong-term immunoprophylactic drugs (e.g. vaccines) and remains the goalof much long-term immunotherapeutic drug development.

In order for cells to perform their functions within the complex systemsof an animal, the cells need to have ‘receptors’ on their surfaces.These receptors are capable of ‘recognising’ specific substances thatcontrol various essential processes such as activation, proliferationand adherence to other cells or substrates. For example, in the case ofthe immune system, the receptors on T and B cells allow them not only torecognise antigen but also to interact with each other and thus regulatetheir activities. Without these receptors, the cells would lack anessential means of communication and would be unable to act effectivelyin the concerted way that is essential for the immune system of amulticellular organism.

In order to be able to specifically recognise and deal with the widerange of pathogens present in the environment, the immune system hasdeveloped two types of highly variable antigen receptor on lymphocytes:antibodies in B cells and T cell receptors, or TCRs, in T cells.

There are a great many different possible antigen receptors present inthe body, to enable the immune system to recognise a wide variety ofinvading pathogens. In fact there are approximately 10¹² different Bcells and T cell receptors in an individual. Each individual B cell hasonly one type of receptor, and so to deal with a particular pathogen, aB cell having the ‘best fitting’ receptor for an antigen of thatpathogen must be selected. This process is termed ‘clonal selection’. Intheory, only a single clone may respond (a monoclonal response) orseveral (an oligoclonal response) or many (a polyclonal response)depending on the number of antigens/epitopes exhibited by the pathogen,and the specificity of the various selected B cells to theseantigen/epitopes.

There is a major difference between the types of antigen that can berecognised by B cells and T cells. As far as it is known, only thereceptors on the surface of B lymphocytes (i.e. antibodies) are capableof directly recognising antigens such as proteins on viruses andbacteria, or foreign molecules dissolved in body fluid. Antibodies canalso be produced in a soluble form by the B cells when they areactivated and develop into plasma cells. The antibodies are also termedimmunoglobulins (abbreviated to Ig). T cell receptors, on the otherhand, recognise only short peptides, also known as T cell epitopes, onthe surface of cells of the body. These T-cell epitopes are produced bydegradation of larger proteins that are either self (i.e. naturallyoccurring body proteins) or non-self (i.e. derived from foreignorganisms infecting the body). Only those derived from foreign proteins,i.e. antigens, are normally capable of inducing an immune response inthe body. Once produced, these epitopes are bound to a special type ofmolecule, the MHC (major histocompatibility complex) and the resultingcomplex is then presented on the cell surface for binding the T cellreceptor.

It should be clear that due to the destructive nature of the immuneresponse, the response has to act only against foreign pathogens, notagainst the body's own cells or proteins. Thus, the immune system needsto distinguish between ‘self’ and ‘non-self’. It has been proposed thatalthough clones of lymphocytes reacting against self are produced, theyare deleted before any reaction can occur. This process is termed‘clonal deletion’. It has also been proposed that any self-reactinglymphocytes could be retained but only in a ‘switched-off’ state. Thismechanism is termed ‘clonal anergy’. Whatever the process considered, itremains unclear what is the exact underlying mechanism allowing lymphoidtissues, such as the thymus, to identify individual T cell clonesreacting against self from the pool of T lymphocytes reacting onlyagainst non-self. The present inventors have now investigated more fullythe mechanism of self/non-self discrimination, which has led to thedevelopment of the present invention. The inventors have now establisheda method of predicting the immunogenicity of a substance such as apeptide, which has enabled quicker identification of immunogenic peptidesequences within large proteins.

It has been known for many years that the major histocompatibilitycomplex (MHC) plays a key role in the immune system of animals. The MHCmolecules enable T cells to recognise antigens, as has already beendiscussed above. There are three general types of MHC molecule, class I,class II and class III. Class I and class II MHC molecules areglycoproteins that are present on the surface of the cell, whilst classIII are usually soluble molecules present inside the cell. There are alarge number of different types of MHC molecule. For example in humans(where MHC is termed HLA, human leukocyte antigen) there are severalhundreds of different alleles of the genes coding for MHC molecules,meaning that in the human population there are many different types ofHLA. The MHC of different species is typically named according todifferent conventions, thus MHC for mouse is termed H-2, for rat RT1 andfor rabbit RLA. The different gene regions coding for different MHCmolecules in an individual are usually individually named, such asHLA-A, HLA-C etc. in humans.

The MHC molecule is a critical immune system molecule, since it is thismolecule that presents the epitopes of the antigens to the immunesystem. For example, if a T cell is to respond to a particular pathogen,the pathogen must have a least one antigen (such as a protein) that hasat least one epitope (such as a peptide portion of the protein) that canbind to an MHC molecule on the surface of a cell and thus interact witha T cell which binds to the MHC-peptide complex. Thus, the immuneresponse is dependent on the ability of the MHC to bind to an epitope.If there is no epitope that the MHC will bind to, or if there is no Tcell which will bind to the MHC-peptide complex, then no immune responsewill occur.

In respect of ‘self’ proteins, however, one of several epitopes may beable to bind to the MHC molecule and hence potentially induce an immuneresponse. On these occasions a specific “signal” must be provided forthe self-reacting lymphocyte clones to be deleted or “switched off”.

Since, as indicated above, both self and foreign (i.e. non-self)peptides can bind to MHC molecules, the binding of various peptides toMHC molecules has received particular scrutiny in the immunology field.Many investigations have sought to calculate or predict the strength ofbinding between certain MHC (particularly HLA and H-2) types and peptidesequences, to try to account for immune responses, or the lack of them(i.e. the “signal” required for discrimination between self andforeign). Examples of these include the following: Altuvia Y, SchuelerO, Margalit H. 1995. “Ranking potential binding peptides to MHCmolecules by a computational threading approach”. J. Mol. Biol.,249:244-250. Altuvia Y, Sette A, Sidney J, Southwood S, Margalit H.1997. “A structure-based algorithm to predict potential binding peptidesto MHC molecules with hydrophobic binding pockets”. Hum. Immunol. 58:1-11. G. E. Meister, C. G. P. Roberts, J. A. Berzofsky, A. S. De Groot,“Two novel T cell epitope prediction algorithms based on MHC-bindingmotifs; comparison of predicted and published epitopes fromMycobacterium tuberculosis and HIV protein sequences” Vaccine,13:581-591, (1995). Gulukota K, Sidney J, Sette A, DeLisi C. 1997. “Twocomplementary methods for predicting peptides binding majorhistocompatibility complex molecules”. J. Mol. Biol. 267:1258-1267.Pamer E G, Harty J T, Bevan M J. “Precise prediction of a dominant classI MHC-restricted epitope of Listeria monocytogenes”. Nature 1991; 353:852-855. Parker K C, Bednarek M A, Coligan J E. 1994. “Scheme forranking potential HLA-A2 binding peptides based on independent bindingof individual peptide side-chains”. J. Immunol. 152:163-175. Rammensee HG, Friede T, Stevanoviic S. 1995. “MHC ligands and peptide motifs: Firstlisting”. Immunogenetics 41:178-228. Ruppert J, Sidney J, Celis E, KuboR T, Grey H M, Sette A. 1993. “Prominent role of secondary anchorresidues in peptide binding to HLA-A2.1 molecules”. Cell 74:929-937.Schueler-Furman O, Elber R, Margalit H. 1998. “Knowledge-based structureprediction of MHC class I bound peptides: A study of 23 complexes”. FoldDes. 3:549-564. Sette A, Buus S, Appella E, Smith J A, Chesnut R, MilesC, Colon S M, Grey H M. 1989. “Prediction of major histocompatibilitycomplex binding regions of protein antigens by sequence patternanalysis”. Proc. Natl. Acad. Sci. USA 86:3296-3300. Sette A, Sidney J,del Guercio M F, Southwood S, Ruppert J, Dahlberg C, Grey H M, Kubo R T.1994a. “Peptide binding to the most frequent HLA-A class I allelesmeasured by quantitative molecular binding assays”. Mol. Immunol.31:813-822. Sette A, Vitiello A, Reherman B, Fowler P, Nayersina R, KastW M, Melief C J M, Oseroff C, Yuan L, Ruppert J, et al. 1994b. “Therelationship between class I binding affinity and immunogenicity ofpotential cytotoxic T cell epitopes”. J. Immunol. 153:5586-5592. StefanStevanovic (2002): “Structural basis of immunogenicity”, TransplantImmunology 10 133-136. Sturniolo T, Bono E, Ding J, Raddrizzani L,Tuereci O, Sahin U, Braxenthaler M, Gallazzi F, Protti M P, SinigagliaF, Hammer J. 1999. “Generation of tissue-specific and promiscuous HLAligand databases using DNA microarrays and virtual HLA class IImatrices”. Nat. Biotechnol. 17:555-561. T. Sudo, N. Kamikawaji, A.Kimura, Y. Date, C. J. Savoie, H. Nakashima, E. Furuichi, S. Kuhara, andT. Sasazuki, “Differences in MHC Class I self peptide repertoires amongHLA-A2 subtypes.” J. Immunol.: 155: 4749-4756, (1995). T. Tana, N.Kamikawaji, C. J. Savoie, T. Sudo, Y. Kinoshita, T. Sasazuki, “A HLAbinding motif-aided peptide epitope library: A novel library design forthe screening of HLA-DR4-restricted antigenic peptides recognized byCD4⁺ T cells.” J. Human Genet., 43:14-21 (1998). K. Falk, et al.“Allele-specific motifs revealed by sequencing of self-peptides elutedfrom MHC molecules”, Nature, Vol. 351, 290-297 (1991). T Elliott et al.“Peptide-induced conformational change of the class I heavy chain”,Nature, Vol. 351, 402-407, (1991). P. Parham, “Deconstructing the MHC”,Nature, Vol. 360, 300-301, (1992). Hwai-Chen Guo et al., “Differentlength peptides bind to HLA-Aw68 similarly at their ends but bulge outin the middle”, Nature, Vol. 360, 364-367, (1992). Y. Chen et al.“Naturally processed peptides longer than nine amino acid residues bindto the class I MHC molecule HLA-A2.1 with high affinity and in differentconformations”, J. Immunol., 152, 2874-2881, (1994). D. F. Hunt et al.“Characterization of peptides bound to the class I MHC molecule HLA-A2.1by mass spectrometry”, Science, Vol. 255, 1261-1263, (1992).

Generally, the prior art attempts to predict the immunogenicity ofparticular peptides by calculating the strength of binding between thatpeptide and the known binding environment of a particular MHC molecule.The binding environment involves a ‘pocket’ in the MHC molecule that isadapted to accept a peptide of a certain length (such as 7-15 aminoacids). The structure of the pocket may already be known from previousX-ray crystallographic studies. This strength may be calculatedmathematically using appropriate algorithms for atomic and molecularinteraction. Alternatively, the prior art may attempt to ‘score’ thebinding strength of a peptide based upon motifs existing in the peptide,such as particular amino acids being present at particular positions ina peptide of a certain length, e.g. a proline present at position 3 inan 8-amino acid peptide binding to a particular known HLA molecule.Generally these approaches have met with limited success.

The present inventors believe that they have improved upon the abovetheories from a better understanding of how T cells reacting againstself-substances such as self-proteins are identified prior to theirelimination (clonal deletion) or silencing (clonal energy). Accordingly,the inventors have been able to identify specific immunogenic peptidesequences that may provide protection against specific pathogens, andhave developed vaccines to these pathogens, using the identifiedsequences. In the case of the present invention, the inventors havedeveloped peptides useful in influenza vaccines eliciting a T cellresponse.

Previously, influenza vaccines have been developed by identifying anexisting influenza virus strain and then producing a vaccine specific tothat virus. Generally, the vaccines have been based upon a B cell(antibody) response, the antibody being reactive with the surfaceantigens (i.e. Hemagglutinin and Neuraminidase) of the specificinfluenza virus strain against which it has been developed. Typically,the surface proteins comprising the antigens are variable from oneinfluenza virus strain to the next, since mutation of the virus toproduce a new virus tends to occur in the surface proteins. Theconsequence of this is that conventional influenza vaccines generallyprotect only against one specific virus strain, and will not protectagainst a new strain that results from a mutation. Thus, a new vaccineis required for protection against an emerging strain. The clear problemwith this approach is that there is a period of time between emergenceof the new virus strain, and development of the vaccine, during whichthere is no protection available against the virus. If the virus isparticularly harmful, this can lead to many millions of deaths, asoccurred in the major influenza pandemics of the last century.

It has been known for some time that cytotoxic T lymphocytes may providean immune response to influenza virus strains. Recent studies have shownthat a CTL response in humans may be directed towards multiple epitopes.It has been suggested that there is a dominant response to the HLA-A2restricted M-1 58-66 epitope. Such studies include A. C. Boon et al, J.Virol, January 2002, 582-90; S. Tamura et al Jpn. J. Infect. Dis.,December 2004, 236-47; G. Deliyannis et al J. Virol., May 2002, 4212-21;C. Gianfrani et al Hum. Immunol., May 2000, 438-52; and J. Jameson et alJ. Immunol., June 1999, 7578-83.

There has recently also been investigation into specific immunogenicpeptides that might be useful in developing an influenza vaccineeliciting a T cell response. Typically, such work has involvedinvestigation of CTL response to test influenza peptides, e.g. intransgenic mice. The tested peptides tend to be short sequences thatmight be reactive to one MHC (or HLA) type, and are taken from aspecific test influenza strain. For example, in Vaccine, 2005, 5231-44,N. Hu et al disclose testing wild type M1 58-66 peptide in HLA Tg miceexpressing HLA-A2, -B7 or -B27. The results show that the peptide is aninfluenza epitope recognised by transgenic mice expressing HLA-A2. InClin. Exp. Immunol., October 2005, 45-52, A. C. Boon et al disclose M158-66 and NP 44-52 influenza A peptides as epitopes recognised inHLA-A*0101 and HLA-A*0201 individuals. In Cell Immunol., April 2005,110-123, E. Cheuk et al disclose NP 383-391 influenza A peptide as anepitope recognised in HLA-B27/H2 class I-deficient mice. Using epitopeprediction programs, the authors identified three more B27 restrictedinfluenza A epitopes, BP-2 702-710, PB-1 571-579 and PB-2 368-376. In J.Immunol., February 2004, 2453-60, A. C. Boon et al disclose human CTLclones specific for natural variants of the HLA-B*3501-restrictedepitope in NP 418-426. In J. Immunother., January-February 2003, 41-6,A. Trojan et al disclose the HLA-A3-restricted 9-mer which is capable ofinducing specific CTL reactivity. HLA-A2 restricted influenza A virusmatrix peptide GILGFVFTL is also disclosed. In J. Gen. Virol., July2001, 1749-55, S. Tourdot et al identify a murine D(k) restrictedepitope derived from the influenza virus strain A/PR/8/34 polymeraseprotein PB-1, corresponding to amino acid residues 349-357. In J.Immunol., April 2001, 4627-33, G. T. Belz et al identify an immunogenicpeptide (SSYRRPVGI) from influenza polymerase protein PB-1,corresponding to amino acid residues 703-711 and a mimotope from PB-2polymerase. PCT/US2005/002954 discloses CTL epitopes comprising NP265-273 and also epitopes comprising NP 305-313. Finally, U.S. Pat. No.6,740,325 discloses two CTL epitopes: NP 335-350, and NP 380-393.

Further studies have shown that data from transgenic mice provide areliable model for the investigation of CTL responses in humans. In Int.Immunol., April 1995, 597-605, S. Man et al have shown that the dominantinfluenza A epitope recognised by HLA-A2.1-restricted cytotoxic Tlymphocytes from HLA-A2.1 transgenic mice was the matrix protein 1 (M-1)peptide epitope that is immunodominant in human CTL responses. Furtherstudies in this area have been conducted by E. J. Bernhard et al (J.Exp. Med., September 1998, 1157-62) and E. Cheuk et al (J. Immunol.,November 2002, 5571-80).

However, although known epitopes have been studied extensively, none hasyet been satisfactory for forming the basis of an influenza vaccine thatis capable of protecting against more than a single strain of influenzavirus. Moreover, vaccines based upon these single epitopes, even if theywere to provide some protection, would likely be specific for aparticular HLA, making them ineffective in a large proportion of thehuman population.

Thus, a significant problem with known vaccines, whether relying on aB-cell or T-cell response is that they only protect against an existingvirus strain, and do not provide protection against possible futurestrains that might develop. With the emergence of the highly dangerousH5N1 strain in the avian population, the need for a vaccine in advanceof a human pandemic based upon a subsequent mutation of the H5N1 strainhas become more acute. Moreover, vaccines based upon known peptideseliciting T-cell responses may not be effective in large sections of thepopulation.

Accordingly, it is an aim of the present invention to solve the problemsassociated with the known prior art as set out above. It is a furtheraim of the present invention to provide a polypeptide that is capable ofeliciting a CTL immune response in vertebrates against a plurality ofinfluenza strains and/or in a plurality of individuals expressingdiffering MHCs (HLAs). It is a further aim of the present invention toprovide an influenza vaccine using the polypeptide of the invention.Preferably the vaccine is capable of protection against a plurality ofinfluenza strains and/or is effective in a plurality of individualsexpressing differing MHCs (HLAs).

Accordingly, the present invention provides a polypeptide having no morethan 100 amino acids, which polypeptide comprises one or more sequenceshaving at least 60% homology with any of SEQ ID 1-6, or comprises two ormore epitopes having 7 amino acids or more, each epitope having at least60% homology with a sub-sequence of any of SEQ ID 1-6 that has the samelength as the epitope:

SEQ ID 1 DLEALMEWLKTRPILSPLTKGILGFVFTLTVP SEQ ID 2LLYCLMVMYLNPGNYSMQVKLGTLCALCEKQASHS  SEQ ID 3 DLIFLARSALILRGSVAHKSC SEQ ID 4 PGIADIEDLTLLARSMVVVRP SEQ ID 5LLIDGTASLSPGMMMGMFNMLSTVLGVSILNLGQ  SEQ ID 6 IIGILHLILWILDRLFFKCIYRLF 

wherein, the polypeptide is immunogenic in a vertebrate expressing amajor histocompatibility complex (MHC) allele, and wherein thepolypeptide is not a complete influenza virus protein.

Thus, the polypeptide is one that may comprise the whole of (or maycomprise at least two 7 or more residue parts of) any of the abovesequences, but cannot have more than 100 amino acid residues in total.The polypeptide must also be immunogenic in a vertebrate expressing anMHC (HLA in humans) allele. An immunogenic polypeptide is understood inthe present context to mean a polypeptide that elicits an immuneresponse in a vertebrate, such as by binding to a vertebrate MHC andcausing it to react with a cytotoxic T cell lymphocyte. One method fordetermining whether a polypeptide possesses immunogenicity is set out inExperiment 1 below. However, the present invention is not limited tosuch methods, and the skilled person may select any known method fordetermining immunogenicity, as desired.

As mentioned above, the polypeptide may be one comprising two 7 or moreresidue epitopes that react with one or more MHCs and so elicit a broadCTL response. The response may be in a single individual or may be in atleast two different individuals (and the individuals may be of the samespecies or different species). Thus, the polypeptide may comprise atleast two different 7 or more residue epitopes, each of whichindividually provides a response to a different subject. An epitope inthe context of the present invention is a part of a polypeptide which iscapable of binding to a vertebrate MHC in a vertebrate, preferablyeliciting an immune response, such as by causing the MHC-epitope complexto react with a CTL. One method for determining whether a polypeptide isor contains an epitope is set out in Experiment 1 below. However, thepresent invention is not limited to such methods, and the skilled personmay select any known method for determining whether a polypeptide is orcontains an epitope, as desired.

The present inventors have found that the above sequences comprise aplurality of CTL epitopes, which may afford protection against influenzafor a wide variety of vertebrates in a population. In addition, theinventors have analyzed all known influenza virus strain sequencesacross all species, and have found that the specified sequences areremarkably conserved across all known influenza virus strains. As such,these sequences are very unlikely to be significantly altered in newstrains resulting from mutation of existing strains. Accordingly, theepitopes within these sequences that provide protection are highlylikely to be present in unchanged form in new strains, since mutationdoes not normally occur in these regions. Consequently, these epitopesprovide excellent opportunity not only for providing protection againstexisting influenza strains (such as the H5N1 strain of ‘bird flu’), butalso protecting against as yet unknown strains (such as a mutated formof H5N1 that could pass easily from human to human and form the basis ofa pandemic).

As discussed above, the sequences have been identified after analysis ofall known influenza virus strain sequences across all species. Thesequences are thus consensus sequences developed from the aboveanalysis. Despite being consensus sequences, the sequences in some casescorrespond exactly to natural sequences in some of the known influenzavirus strains. Due to the remarkable conservation in the sequencesacross all viruses in all species, the consensus sequences, even whendiffering from actual sequences, only differ in a small number ofresidues, and thus contain many smaller epitopes (8-mers, 9-mers,10-mers etc.) for which there are no differences from natural sequences.The above consensus sequences as a whole thus contain many effectiveepitopes that are the same as the natural epitopes, as well as effectiveepitopes that differ only slightly from natural epitopes. It will beapparent to the skilled person that the invention extends not only tothe consensus sequences and their epitopes, but also to thecorresponding actual sequences in any influenza virus strains. Thus,sequences with some homology to the consensus sequences are also withinthe scope of the invention. Such homology allows substitution of, forexample, up to 3 amino acids in an 8-mer epitope (62.5% homology) or ina 9-mer, 10-mer, or 11-mer epitope. It is preferred that no more than 10such substitutions are identifiable in a sequence of the inventioncorresponding to the full sequences of SEQ ID 1-6 (66.6% homology for a30-mer). Such substitutions are preferably conservative substitutions inline with known substitution schemes.

Having in mind that the invention extends from the consensus sequence tothe corresponding natural sequences, then the invention also provides apolypeptide having no more than 100 amino acids, which polypeptidecomprises one or more sequences defined by the following amino acidresidues of an influenza virus protein, or comprises two or moreepitopes having 7 amino acids or more from a sequence defined by thefollowing amino acid residues of an influenza virus protein:

residues 36-75 of an M1 protein (preferably from an influenza A strain)residues of an M1 protein (preferably from an influenza B strain)124-158 residues of an NP protein (preferably from an influenza Astrain) 255-275 residues of an NP protein (preferably from an influenzaB strain) 306-326 residues of a PB1 protein residues 32-55 of an M2protein 395-428

wherein, the polypeptide is immunogenic in a vertebrate expressing amajor histocompatibility complex (MHC) allele, and wherein thepolypeptide is not a complete influenza virus protein.

The sequence numbering referred to in the present invention is definedaccording to well-recognised principles. Thus, the numbering begins at 1from the recognised translation initiation codon (ATG). This correspondsto a Methionine (M), for the segment of the Influenza genome coding forthe protein of interest. In other words, it begins at 1 in respect ofthe Methionine shown as the first amino acid in the protein sequence ofinterest as used and defined by the databases in which the sequenceshave been set forth (i.e. GenBank, SwissProt, etc.).

The present invention will be described in more detail by way of exampleonly with reference to the following Figures, in which:

FIG. 1A to 1F show IFN-γ production by primary splenocyte cultures ofFLU-v and NRP vaccinated mice stimulated with Con A (10 μg/ml), solubleLysozyme (5 μg/ml), purified soluble polypeptides (P1 (FIG. 1A), P2(FIG. 1B), P3 (FIG. 1C), P4 (FIG. 1D), P5 (FIG. 1E) and P6 (FIG. 1F); 5μg/ml) and HLA-matched T1 (T1) and mismatched JURKAT (Ju) human cellstransfected with either Lysozyme, P1, P2, P3, P4, P5 or P6 according tothe protocol described in Example 1 below (splenocyte to transfectedcell ratio is 10:1). IFN-γ production is represented as the differentialbetween the level of production in response to the antigen consideredminus the IFN-γ produced in response to either soluble Lysozyme or thecorresponding cell transfected with Lysozyme. Background levels ofLysozyme mediated production of IFN-γ were for soluble antigen 25±10μg/ml, for antigen in T1 316±43 μg/ml, and for antigen in Jurkat 19±6μg/ml;

FIG. 2 shows IFN-γ production by primary splenocyte cultures of FLU-vand NRP vaccinated mice stimulated with Con A (10 μg/ml), solubleLysozyme (5 μg/ml), purified soluble FLU-v polypeptide preparation (P1,P2, P3, P4, P5 and P6 all together at 5 μg/ml) and HLA-matched T1 (T1)and mismatched JURKAT (Ju) human cells either infected with influenzastrains A/New_Calcdonia/20/99, A/NYMC/X-147 or B/Johannesburg/5/99 ortransfected with Lysozyme according to the protocol described in Example1 below (splenocyte to infected/transfected cell ratio is 10:1); IFN-γproduction is represented as the differential between the level ofproduction in response to the antigen considered minus the IFN-γproduced in response to either soluble Lysozyme or the correspondingcell transfected with Lysozyme; background levels of Lysozyme mediatedproduction of IFN-γ were for soluble antigen 25±10 μg/ml, for antigen inT1 316±43 μg/ml, and for antigen in Jurkat 19±6 μg/ml; and

FIGS. 3A and 3B show survival of animals following a lethal challengewith Influenza A/PR/8/34; animals were immunised subcutaneously witheither FLU-v or NRP-v on days 1 and 15 and on day 20 all were challengedintranasally with 45 μl of the virus (5×10⁷ pfu per dose) underanaesthesia; animals in FIG. 3A were inoculated intraperitoneally with100 μg of rat anti-mouse CD8 sera on days 19 and 22; animals in FIG. 3Bwere inoculated intraperitoneally with an irrelevant rat sera on days 19and 22; the arrow indicates the date of intranasal challenge whilst thediamonds indicate the date animals were inoculated with the anti-CD8sera.

FIG. 4 shows Scheme 1 innoculation.

FIG. 5 shows Scheme 2—control test for T1 and JURKAT.

FIG. 6 shows Scheme 3—FLU-v test for T1 and JURKAT.

The polypeptide described above typically comprises one or more(preferably two or more) epitopes. These epitopes are preferably T cellepitopes, such as cytotoxic T lymphocyte (CTL) epitopes. Generally thepolypeptide is immunogenic to an influenza virus strain, and preferablyto a plurality of influenza virus strains. In the present context, apolypeptide immunogenic to an influenza virus strain is understood tomean a polypeptide that is part of an influenza virus protein and thatelicits an immune system response, such as by exhibiting CTL reactivitywhen bound to an MHC. One method for determining whether a polypeptidepossesses such immunogenicity is set out in Experiment 1 below. However,the present invention is not limited to such methods, and the skilledperson may select any known method for determining immunogenicity, asdesired.

In the present invention, the polypeptide comprises two or moresequences as described above. Typically, two, three, four, five or moresuch sequences may be present in the polypeptide, if desired. The moresuch epitopes are present, the greater the breadth of protectionafforded within a population of humans and/or animals individuals withdiffering HLAs or MHCs.

The polypeptide according to the present invention may also comprise oneor more further sequences that are not epitopes, if desired. Typicallythe further sequences are from one or more influenza virus proteins.These sequences may be situated between two or more of the sequences(the epitopes) described above, or may be situated at one or both endsof the polypeptide. The presence of such further sequences should notaffect the function of the polypeptide, provided that the polypeptide asa whole does not become too large, interfering with the presentation ofthe epitopes in the vertebrate's immune system. In specific embodimentsof the invention, when the polypeptide is homologous to SEQ ID 1, thefurther sequences are preferably one or more from an influenza M1protein (preferably from an influenza A strain), when the polypeptide ishomologous to SEQ ID 2, the further sequences are preferably one or morefrom an influenza M1 protein (preferably from an influenza B strain),when the polypeptide is homologous to SEQ ID 3, the further sequencesare preferably one or more from an influenza NP protein (preferably froman influenza A strain), when the polypeptide is homologous to SEQ ID 4,the further sequences are preferably one or more from an influenza NPprotein (preferably from an influenza B strain), when the polypeptide ishomologous to SEQ ID 5, the further sequences are preferably one or morefrom an influenza PB1 protein, and when the polypeptide is homologous toSEQ ID 6, the further sequences are preferably one or more from aninfluenza M2 protein.

In the most preferred embodiments, the further sequences from theabove-mentioned proteins are ones within the following consensussequences, or ones having at least 60% homology with a sequence withinthe following consensus sequences:

M1 Influenza A Consensus- SEQ ID 7MSLLTEVETYVLSIVPSGPLKAEIAQRLEDVFAGKNTDLEALMEWLKTRPILSPLTKGILGFVF TLTVPSERGLQRRRFVQNALNGNGDPNNMDKAVKLYRKLKREITFHGAKEIALSYSAGALASCM GLIYNRMGAVTTEVAFGLVCATCEQIADSQHRSHRQMVATTNPLIKHENRMVLASTTAKAMEQM AGSSEQAAEAMEIASQARQMVQAMRTVGTHPSSSTGLRDDLLENLQTYQKRMGVQMQRFK M1 Influenza B Consensus- SEQ ID 8MSLFGDTIAYLLSLTEDGEGKAELAEKLHCWFGGKEFDLDSALEWIKNKRCLTDIQKALIGASICFLKPKDQERKRRFITEPLSGMGTTATKKKGLILAERKMRRCVSFHEAFEIAEGHESSALLYCL MVMYLNPGNYSMQVKLGTLCALCEKQASHSHRAHSRAARSSVPGVRREMQMVSAMNTAKTMNGM GKGEDVQKLAEELQSNIGVLRSLGASQKNGEGIAKDVMEVLKQSSMGNSALVKKYL NP Influenza A Consensus- SEQ ID 9MASQGTKRSYEQMETDGDRQNATEIRASVGKMIDGIGRFYIQMCTELKLSDYEGRLIQNSLTIE KMVLSAFDERRNRYLEEHPSAGKDPKKTGGPIYRRVDGKWMRELVLYDKEEIRRIWRQANNGED ATAGLTHMMIWHSNLNDATYQRTRALVRTGMDPRMCSLMQGSTLPRRSGAAGAAVKGIGTMVME LIRMIKRGINDRNFWRGENGRKTRSAYERMCNILKGKFQTAAQRAMVDQVRESRNPGNAEIEDL IFLARSALILRGSVAHKSCLPACVYGPAVSSGYDFEKEGYSLVGIDPFKLLQNSQVYSLIRPNE NPAHKSQLVWMACHSAAFEDLRLLSFIRGTKVSPRGKLSTRGVQIASNENMDNMGSSTLELRSG YWAIRTRSGGNTNQQRASAGQISVQPTFSVQRNLPFEKSTVMAAFTGNTEGRTSDMRAEIIRMM EGAKPEEVSFRGRGVFELSDEKATNPIVPSFDMSNEGSYFFGDNAEEYDN NP Influenza B Consensus- SEQ ID 10MSNMDIDGINTGTIDKTPEEITSGTSGTTRPIIRPATLAPPSNKRTRNPSPERATTSSEADVGR KTQKKQTPIEIKKSVYNMVVKLGEFYNQMMVKAGLNDDMERNLIQNAHAVERILLAATDDKKTE FQKKKNARDVKEGKEEIDHNKTGGTFYKMVRDDKTIYFSPIRITFLKEEVKTMYKTTMGSDGFS GLNHIMIGHSQMNDVCFQRSKALKRVGLDPSLISTFAGSTLPRRSGATGVAIKGGGTLVAEAIR FIGRAMADRGLLRDIKAKTAYEKILLNLKNKCSAPQQKALVDQVIGSRNPGIADIEDLTLLARS MVVVRPSVASKVVLPISIYAKIPQLGFNVEEYSMVGYEAMALYNMATPVSILRMGDDAKDKSQL FFMSCFGAAYEDLRVLSALTGTEFKPRSALKCKGFHVPAKEQVEGMGAALMSIKLQFWAPMTRS GGNEVGGDGGSGQISCSPVFAVERPIALSKQAVRRMLSMNIEGRDADVKGNLLKKMNDSMAKKT NGNAFIGKKMFQISDKNKTNPVEIPIKQTIPNFFFGRDTAEDYDDLDY PB1 Influenza Consensus- SEQ ID 11MDVNPTLLFLKVPAQNAISTTFPYTGDPPYSHGTGTGYTMDTVNRTHQYSEKGKWTTNTETGAPQLNPIDGPLPEDNEPSGYAQTDCVLEAMAFLEESHPGIFENSCLETMEVVQQTRVDKLTQGRQT YDWTLNRNQPAATALANTIEVFRSNGLTANESGRLIDFLKDVMESMDKEEMEITTHFQRKRRVR DNMTKKMVTQRTIGKKKQRVNKRGYLIRALTLNTMTKDAERGKLKRRAIATPGMQIRGFVYFVE TLARSICEKLEQSGLPVGGNEKKAKLANVVRKKMINSQDTELSFTITGDNTKWNENQNPRMFLA MITYITKNQPEWFRNILSIAPIMFSNKMARLGKGYMFESKRMKLRTQIPAEMLASIDLKYFNESTRKKIEKIRPLLIDGTASLSPGMKMGMFNMLSTVLGVSILNLGQKKYTKTTYWWDGLQSSDDFA LIVNAPNHEGIQAGVDRFYRTCKLVGINMSKKKSYINKTGTFEFTSFFYRYGFVANFSMELPSF GVSGINESADMSIGVTVIKNNMINNDLGPATAQMALQLFIKDYRYTYRCHRGDTQIQTRRSFEL KKLWDQTQSKAGLLVSDGGPNLYNIRNLHIPEVCLKWELMDEDYRGRLCNPLNPFVSHKEIESV NNAVVMPAHGPAKSMEYDAVATTHSWIPKRNRSILNTSQRGILEDEQMYQKCCNLFEKFFPSSS YRRPVGISSMVEAMVSRARIDARIDFESGRIKKEEFSEIMKICSTIEELRRQKK M2 Influenza Consensus- SEQ ID 12MSLLTEVETPIRNEWGCRCNDSSDPLVVAASIIGILHLILWILDRLFFKCIYRFKHGLKRGPS TEGVPESMREEYRKEQQNAVDADDSHFVSIELE 

The homology referred to above in respect of these sequences ispreferably 75%, 85%, 95% or substantially 100%.

In the present invention, the influenza strain is not especiallylimited, and the polypeptides may be immunogenic against, and/or derivedfrom, any known influenza strain. Preferably, however, the relevantstrain is an Influenza A or Influenza B strain. Future influenza strainsthat have mutated from any of these existing strains may also be onesagainst which the polypeptides are immunogenic, or from which thepolypeptides are derived.

The proteins within which the sequences defining the polypeptides of thepresent invention are situated are selected from M1, NP, PB and M2proteins from any influenza virus strain (especially A and B strains)(the consensus sequences of which for all analyzed sequences, oralternatively the positions of which within the protein, are describedabove). The following specific proteins were analyzed by the inventors,and preferably the influenza virus proteins referred to in the inventionare selected from these specific proteins, or mutations from theseproteins. Thus, the specific sequences homologous to SEQ ID 1-6described above are preferably the ones at the appropriate positionswithin the following proteins. Similarly, the sequences of the presentinvention defined by the residue positions within proteins from anyinfluenza strain, namely residues 36-75 of M1 protein (especiallyinfuenza A M1), residues 124-158 of M1 protein (especially in influenzaB M1), residues 255-275 of NP protein (especially in influenza A NP),residues 306-326 of NP protein (especially in influenza B NP), residues395-428 of PB1 protein, and residues 32-55 of M2 protein, are preferablythose within the following specific proteins. The list is in the form|version number (gi number)|database identification (e.g. gb forGenBank)|NCBI accession number|optional further information (e.g. theaccession number of the nucleotide sequence from which the proteinsequence is derived). The sequences and corresponding influenza strainsfrom which they derive can all be found from the public NCBI proteindatabase. The protein database contains sequence data from thetranslated coding regions from DNA sequences in GenBank, EMBL, and DDBJas well as protein sequences submitted to Protein Information Resource(PIR), SWISS-PROT, Protein Research Foundation (PRF), and Protein DataBank (PDB) (sequences from solved structures).

M1 proteins |27530653|dbj|BAC54009.1|;  |27530634|dbj|BAC53998.1|;|53829719|gb|AAU94746.1|; |53829716|gb|AAU94744.1|; |53829713|gb|AAU94742.1|; |53829710|gb|AAU94740.1|;|53829707|gb|AAU94738.1|;  |53829704|gb|AAU94736.1|;|53829701|gb|AAU94734.1|; |53829698|gb|AAU94732.1|; |53829695|gb|AAU94730.1|; |53829692|gb|AAU94728.1|;|53829689|gb|AAU94726.1|;  |53829686|gb|AAU94724.1|;|53829683|gb|AAU94722.1|; |8486160|ref|NP_056664.1|;|30466242|ref|NP_848689.1|; |30349250|gb|AAP22121.1|;|30466211|ref|NP_848672.1|; |30349219|gb|AAP22104.1|;|4761025|gb|AAD29208.1|AF100392_1|; |4761022|gb|AAD29206.1|AF100391_1|;|4761019|gb|AAD29204.1|AF100390_1|; |4761016|gb|AAD29202.1|AF100389_1|;|4761013|gb|AAD29200.1|AF100388_1|; |4761010|gb|AAD29198.1|AF100387_1|;|4761007|gb|AAD29196.1|AF100386_1|; |4761004|gb|AAD29194.1|AF100385_1|;|4761001|gb|AAD29192.1|AF100384_1|; |4760998|gb|AAD29190.1|AF100383_1|;|4760995|gb|AAD29188.1|AF100382_1|; |4760992|gb|AAD29186.1|AF100381_1|;|4760989|gb|AAD29184.1|AF100380_1|; |4760986|gb|AAD29182.1|AF100379_1|;|4760983|gb|AAD29180.1|AF100378_1|; |4760980|gb|AAD29178.1|AF100377_1|;|4760977|gb|AAD29176.1|AF100376_1|; |4760974|gb|AAD29174.1|AF100375_1|;|4760971|gb|AAD29172.1|AF100374_1|; |12862823|dbj|BAB32623.1|; |12862820|dbj|BAB32621.1|; |12862817|dbj|BAB32619.1|;|5702096|gb|AAD47140.1|; |51340785|gb|AAU01001.1|;|50059438|gb|AAT69451.1|; |50059400|gb|AAT69429.1|; |50059419|gb|AAT69440.1|; |325196|gb|AAA67100.1|;|325202|gb|AAA43726.1|; |138823|sp|P03489|VMT1_INBLE|;|138824|sp|P06816|VMT1_INBSI|; |138822|sp|P13880|VMT1_INBAD|; |138821|sp|P13879|VMT1_INBAC|; |325198|gb|AAA66416.1|;|325194|gb|AAA66414.1|; |9049382|dbj|BAA99399.1|;|5764368|gb|AAD51265.1|AF153257_1|; |76443315|gb|ABA42441.1|;|76443312|gb|ABA42439.1|; |76443309|gb|ABA42437.1|;|76443306|eb|ABA42435.1|; |76443303|gb|ABA42433.1|;|21636455|gb|AAM70003.1|AF457712_1|;|21636450|gb|AAM70000.1|AF457710_1|;|21636434|gb|AAM69991.1|AF457703_1|;|21636416|gb|AAM69981.1|AF457695_1|;|21636398|gb|AAM69971.1|AF457687_1|;|21636378|gb|AAM69960.1|AF457678_1|; |9802291|gb|AAF99672.1|AF258523_1|;|9802288|gb|AAF99670.1|AF258522_1|; |5764374|gb|AAD51269.1|AF153259_1|;|5805289|gb|AAD51928.1|AF144306_1|; |5764371|gb|AAD51267.1|AF153258_1|;|71655384|gb|AAZ38740.1|;  |71655379|gb|AAZ38738.1|;|71655371|gb|AAZ38736.1|; |71655356|gb|AAZ38734.1|; |71655345|gb|AAZ38732.1|; |71655341|gb|AAZ38730.1|;|71655320|gb|AAZ38728.1|; |73852957|ref|YP_308671.1|;|73912688|ref|YP_308854.1|; |28849409|gb|AAO52887.1|AF509044_1|;|5732422|gb|AAD49093.1|AF156470_2|; |5732419|gb|AAD49091.1|AF156469_2|;|5732416|gb|AAD49089.1|AF156468_2|; |28194354|gb|AAO33517.1|AF474058_1|;|28194351|gb|AAO33515.1|AF474057_1|;|28194348|gb|AAO33513.1|AF474056_1|;|28194345|gb|AAO33511.1|AF474055_1|;|28194342|gb|AAO33509.1|AF474054_1|;|28194339|gb|AAO33507.1|AF474053_1|;|28194336|gb|AAO33505.1|AF474052_1|;|28194333|gb|AAO33503.1|AF474051_1|;|28194330|gb|AAO33501.1|AF474050_1|;|28194327|gb|AAO33499.1|AF474049_1|;|28849451|gb|AAO52908.1|AF509065_1|;|28849449|gb|AAO52907.1|AF509064_1|;|28849447|gb|AAO52906.1|AF509063_1|;|28849445|gb|AAO52905.1|AF509062_1|;|28849443|gb|AAO52904.1|AF509061_1|;|28849441|gb|AAO52903.1|AF509060_1|;|28849439|gb|AAO52902.1|AF509059_1|;|28849437|gb|AAO52901.1|AF509058_1|;|28849435|gb|AAO52900.1|AF509057_1|;|28849433|gb|AAO52899.1|AF509056_1|;|28849431|gb|AAO52898.1|AF509055_1|;|28849429|gb|AAO52897.1|AF509054_1|;|28849427|gb|AAO52896.1|AF509053_1|;|28849425|gb|AAO52895.1|AF509052_1|;|28849423|gb|AAO52894.1|AF509051_1|;|28849421|gb|AAO52893.1|AF509050_1|;|28849419|gb|AAO52892.1|AF509049_1|;|28849417|gb|AAO52891.1|AF509048_1|;|28849415|gb|AAO52890.1|AF509047_1|;|28849413|gb|AAO52889.1|AF509046_1|;|28849411|gb|AAO52888.1|AF509045_1|;|28849407|gb|AAO52886.1|AF509043_1|;|28849405|gb|AAO52885.1|AF509042_1|;|28849403|gb|AAO52884.1|AF509041_1|;|28849401|gb|AAO52883.1|AF509040_1|; |5732407|gb|AAD49083.1|AF156465_2|;|5732425|gb|AAD49095.1|AF156471_2|; |5732413|gb|AAD49087.1|AF156467_2|;|5732410|gb|AAD49085.1|AF156466_2|; |5732404|gb|AAD49081.1|AF156464_2|;|5732401|gb|AAD49079.1|AF156463_2|; |5732398|gb|AAD49077.1|AF156462_2|;|5732395|gb|AAD49075.1|AF156461_2|; |5732392|gb|AAD49073.1|AF156460_2|;|5732389|gb|AAD49071.1|AF156459_2|; |5732386|gb|AAD49069.1|AF156458_2|;|324263|gb|AAA43254.1|;  |37933077|gb|AAO46713.1|;|37933074|gb|AAO46711.1|; |37933071|gb|AAO46709.1|;|37933068|gb|AAO46707.1|; |37933065|gb|AAO46705.1|;|37933062|gb|AAO46703.1|; |37933059|gb|AAO46701.1|;|37933056|gb|AAO46699.1|; |37933053|gb|AAO46697.1|;|37933050|gb|AAO46695.1|; |37933047|gb|AAO46693.1|;|37933044|gb|AAO46691.1|; |37933041|gb|AAO46689.1|;|37933038|gb|AAO46687.1|; |37933035|gb|AAO46685.1|;|37933032|gb|AAO46683.1|; |37933029|gb|AAO46681.1|;|37933026|gb|AAO46679.1|; |37933023|gb|AAO46677.1|;|37933020|gb|AAO46675.1|; |37933017|gb|AAO46673.1|;|37933014|gb|AAO46671.1|; |37933011|gb|AAO46669.1|;|37933008|gb|AAO46667.1|; |37933005|gb|AAO46665.1|;|37933002|gb|AAO46663.1|; |37932999|gb|AAO46661.1|;|37932996|gb|AAO46659.1|; |37932993|gb|AAO46657.1|;|37932990|gb|AAO46655.1|; |37932987|gb|AAO46653.1|;|37932984|gb|AAO46651.1|; |37785163|gb|AAO46420.1|;|37785160|gb|AAO46418.1|; |37785157|gb|AAO46416.1|;|37785154|gb|AAO46414.1|; |37785151|gb|AAO46412.1|;|37785145|gb|AAO46408.1|; |37785142|gb|AAO46406.1|;|37785139|gb|AAO46404.1|; |37785136|gb|AAO46402.1|;|37785133|gb|AAO46400.1|; |37785130|gb|AAO46398.1|;|37785127|gb|AAO46396.1|; |37785124|gb|AAO46394.1|;|37785121|gb|AAO46392.1|; |37785118|gb|AAO46390.1|;|37785115|gb|AAO46388.1|; |37785112|gb|AAO46386.1|;|37785109|gb|AAO46384.1|; |37785106|gb|AAO46382.1|;|37785103|gb|AAO46380.1|; |37785100|gb|AAO46378.1|;|37785097|gb|AAO46376.1|; |37785094|gb|AAO46374.1|;|37785091|gb|AAO46372.1|; |37785088|gb|AAO46370.1|;|37785085|gb|AAO46368.1|; |37785082|gb|AAO46366.1|;|37785079|gb|AAO46364.1|; |37785076|gb|AAO46362.1|;|37785073|gb|AAO46360.1|; |37785070|gb|AAO46358.1|;|37785067|gb|AAO46356.1|; |37785064|gb|AAO46354.1|;|37785061|gb|AAO46352.1|; |37785058|gb|AAO46350.1|;|37785055|gb|AAO46348.1|; |37785053|gb|AAO46347.1|;|37785049|gb|AAO46344.1|; |37785046|gb|AAO46342.1|;|13925107|gb|AAK49251.1|AF255374_1|; |324383|gb|AAA43336.1|;|324322|gb|AAA43294.1|; |325068|gb|AAA43674.1|; |324395|gb|AAA43344.1|;|324371|gb|AAA43316.1|; |324334|gb|AAA43302.1|; |324316|gb|AAA43290.1|; |324310|gb|AAA43286.1|; |324299|gb|AAA43277.1|;|11065886|gb|AAG28376.1|AF188004_1|;|11065883|gb|AAG28374.1|AF188003_1|; |483855|gb|AAC79577.1|;|2833661|gb|AAC34265.1|; |73665375|gb|AAZ79394.1|;|30025987|gb|AAP04510.1|;  |66734259|gb|AAY53536.1|;|37785148|gb|AAO46410.1|; |7429156|pir.parallel.PN0086|; |58618460|gb|AAW80728.1|; |58618458|gb|AAW80727.1|;|13925103|gb|AAK49249.1|AF255373_1|; |50365716|gb|AAT76159.1|;|18140844|gb|AAL60445.1|AF398876_1|; |20065772|gb|AAM09298.1|;|20065769|gb|AAM09296.1|; |324406|gb|AAA43351.1|;|324398|gb|AAA43347.1|; |324392|gb|AAA43342.1|; |324389|gb|AAA43340.1|;|324386|gb|AAA43338.1|; |324380|gb|AAA43334.1|; |324377|gb|AAA43332.1|;|324374|gb|AAA43318.1|; |324344|gb|AAA43307.1|; |324331|gb|AAA43300.1|;|324328|gb|AAA43298.1|; |324319|gb|AAA43292.1|; |324313|gb|AAA43288.1|; |324307|gb|AAA43282.1|; |324304|gb|AAA43280.1|;|27596998|ref|NP_775536.1|; |61612084|gb|AAX47287.1|;|63054907|gb|AAY28990.1|; |60473|emb|CAA30892.1|;|60470|emb|CAA30890.1|; |60467|emb|CAA30888.1|; |60464|emb|CAA30886.1|;|60461|emb|CAA30884.1|; |60458|emb|CAA30882.1|;|45124752|emb|CAF33014.1|;  |94145|pir.parallel.JN0392|;|75117|pir.parallel.MFIV1K|; |7444522|pir.parallel.T09279|; |77195|pir.parallel.S04050|; |77193|pir.parallel.S04052|;|77191|pir.parallel.S04058|; |77189|pir.parallel.S04056|;|56548894|gb|AAV97612.1|; |56548892|gb|AAV97611.1|;|56548890|gb|AAV97610.1|; |56548888|gb|AAV97609.1|;|58618456|gb|AAW80726.1|; |51094108|gb|AAS89185.2|;|51859837|gb|AAU11202.1|; |51859834|gb|AAU11200.1|;|51859831|gb|AAU11198.1|; |51859825|gb|AAU11194.1|;|51859822|gb|AAU11192.1|; |51859819|gb|AAU11190.1|;|51859816|gb|AAU11188.1|; 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|76366076|gb|ABA42273.1|;|76366057|gb|ABA42262.1|; |76366038|gb|ABA42251.1|;|76366019|gb|ABA42240.1|; |75750352|gb|ABA26803.1|;|75750333|gb|ABA26792.1|; |75750314|gb|ABA26781.1|;|58429773|gb|AAW78291.1|; |58429761|gb|AAW78285.1|;|58429759|gb|AAW78284.1|; |50542643|gb|AAT78586.1|;|50083045|gb|AAT70174.1|; |50059188|gb|AAT69352.1|;|55273941|gb|AAV48837.1|; |55233233|gb|AAV48549.1|;|53765727|gb|AAU93405.1|; |51094113|gb|AAS89187.2|;|51859870|gb|AAU11219.1|; |51859868|gb|AAU11218.1|;|51859866|gb|AAU11217.1|; |51859864|gb|AAU11216.1|;|51859862|gb|AAU11215.1|; |51859860|gb|AAU11214.1|;|51859858|gb|AAU11213.1|; |51859856|gb|AAU11212.1|;|51859854|gb|AAU11211.1|; |51859852|gb|AAU11210.1|;|51859850|gb|AAU11209.1|; |51859848|gb|AAU11208.1|;|51859846|gb|AAU11207.1|; |51859844|gb|AAU11206.1|;|51859842|gb|AAU11205.1|; |51859840|gb|AAU11204.1|;|50365720|gb|AAT76161.1|; |47834948|gb|AAT39109.1|;|47834946|gb|AAT39108.1|; |47834944|gb|AAT39107.1|;|47834934|gb|AAT39102.1|; |47834932|gb|AAT39101.1|;|33867359|gb|AAQ55062.1|; |45124766|emb|CAF33022.1|;|45124750|emb|CAF33013.1|; |45124746|emb|CAF33011.1|;|33318065|gb|AAQ04906.1|AF508617_1|;|33318063|gb|AAQ04905.1|AF508618_1|;|33318059|gb|AAQ04903.1|AF508614_1|;|33318055|gb|AAQ04901.1|AF508612_1|; |33318053|gb|AAQ04900.1|AF5086111|;|33318049|gb|AAQ04898.1|AF508609_1|;|33318045|gb|AAQ04896.1|AF508607_1|;|33318043|gb|AAQ04895.1|AF508608_1|;|33318041|gb|AAQ04894.1|AF508605_1|; |41207477|gb|AAR99630.1|;|40732903|emb|CAF04486.1|; |14275699|emb|CAC40041.1|;|21902318|gb|AAM78513.1|AF483604_1|; |13383285|dbj|BAB39514.1|;|13383283|dbj|BAB39513.1|; |5531266|emb|CAB50887.1|;|30043924|gb|AAG01753.2|AF251399_1|;|28849599|gb|AAO52982.1|AF509139_1|;|28849561|gb|AAO52963.1|AF509120_1|;|28849559|gb|AAO52962.1|AF509119_1|;|28849557|gb|AAO52961.1|AF509118_1|;|28849555|gb|AAO52960.1|AF509117_1|; |28820286|gb|AAO46832.1|;|28820284|gb|AAO46831.1|; |28820282|gb|AAO46830.1|;|28820280|gb|AAO46829.1|; |28820278|gb|AAO46828.1|;|28820276|gb|AAO46827.1|; |28820047|gb|AAO46826.1|;|28819610|gb|AAO46825.1|; |28818981|gb|AAO46824.1|;|18496110|emb|CAD20329.1|; |27462153|gb|AAO15349.1|AF225537_1|;|27462151|gb|AAO15348.1|AF225538_1|;|27462149|gb|AAO15347.1|AF225535_1|;|27462147|gb|AAO15346.1|AF225534_1|; |22859439|emb|CAD30201.1|;|22859437|emb|CAD30200.1|; |21359670|gb|AAM49560.1|AF468842_1|;|20068061|emb|CAC85241.1|; |20068055|emb|CAC85238.1|;|20068051|emb|CAC85236.1|; |20068049|emb|CAC85235.1|;|20068037|emb|CAC85229.1|; |19913216|emb|CAD20330.1|;|19913210|emb|CAD20324.1|; |19697806|gb|AAL31404.1|;|19697804|gb|AA131403.1|; |19697802|gb|AAL31402.1|;|19697800|gb|AAL31401.1|; |19697798|gb|AA131400.1|;|19697796|gb|AAL31399.1|; |19697794|gb|AA|31398.1|;|19422139|gb|AAL87896.1|AF455708_1|;|19422137|gb|AAL87895.1|AF455705_1|;|19422135|gb|AAL87894.1|AF455704_1|;|19422131|gb|AAL87892.1|AF455702_1|;|19422129|gb|AAL87891.1|AF455701_1|; |16076709|gb|AAL14085.1|AF222815_1|

PB1 proteins |53829905|gb|AAU94857.1|; |53829903|gb|AAU94856.1|;|53829901|gb|AAU94855.1|; |53829899|gb|AAU94854.1|;|53829897|gb|AAU94853.1|; |53829895|gb|AAU94852.1|;|53829893|gb|AAU94851.1|; |53829891|gb|AAU94850.1|;|53829889|gb|AAU94849.1|; |53829887|gb|AAU94848.1|;|53829885|gb|AAU94847.1|; |53829883|gb|AAU94846.1|;|53829881|gb|AAU94845.1|; |9622317|gb|AAF89734.1|AF170571_1|;|558512|dbj|BAAO0002.1|; |8486165|ref|NP_056657.1|;|30466229|ref|NP_848682.1|; |30466214|ref|NP_848674.1|;|30349237|gb|AAP22114.1|; |30349222|gb|AAP22106.1|;|325276|gb|AAA43767.1|; |67090|pir|P1IVBL|; |50059427|gb|AAT69445.1|;|50059408|gb|AAT69434.1|; |50059389|gb|AAT69423.1|;|6318399|gb|AAF06876.1|AF102007_1|; |6318397|gb|AAF06875.1|AF102006_1|;|6318395|gb|AAF06874.1|AF102005_1|; |6318393|gb|AAF06873.1|AF102004_1|;|6318391|gb|AAF06872.1|AF102003_1|; |6318389|gb|AAF06871.1|AF102002_1|;|6318387|gb|AAF06870.1|AF102001_1|; |6318385|gb|AAF06869.1|AF102000_1|;|6318383|gb|AAF06868.1|AF101999_1|; |6318381|gb|AAF06867.1|AF101998_1|;|6318379|gb|AAF06866.1|AF101997_1|; |6318377|gb|AAF06865.1|AF101996_1|;|6318375|gb|AAF06864.1|AF101995_1|; |6318373|gb|AAF06863.1|AF101994_1|;|6318371|gb|AAF06862.1|AF101993_1|; |6318369|gb|AAF06861.1|AF101992_1|;|6318367|gb|AAF06860.1|AF101991_1|; |68655094|emb|CAG96510.1|;|20126603|gb|AAK95906.1|; |51340771|gb|AAU00993.1|;|133529|sp|P13872|RRP1_INBAD|; |133530|sp|P07832|RRP1_INBLE|;|6647764|sp|O36430|RRP1_INBP9|; |133528|sp|P13871|RRP1_INBAC|;|8486151|ref|NP_056659.1|; |6318433|gb|AAF06893.1|AF102024_1|;|6318431|gb|AAF06892.1|AF102023_1|; |6318429|gb|AAF06891.1|AF102022_1|;|6318427|gb|AAF06890.1|AF102021_1|; |6318425|gb|AAF06889.1|AF102020_1|;|6318423|gb|AAF06888.1|AF102019_1|; |6318421|gb|AAF06887.1|AF102018_1|;|6318419|gb|AAF06886.1|AF102017_1|; |6318417|gb|AAF06885.1|AF102016_1|;|6318415|gb|AAF06884.1|AF102015_1|; |6318413|gb|AAF06883.1|AF102014_1|;|6318411|gb|AAF06882.1|AF102013_1|; |6318409|gb|AAF06881.1|AF102012_1|;|6318407|gb|AAF06880.1|AF102011_1|; |6318405|gb|AAF06879.1|AF102010_1|;|6318403|gb|AAF06878.1|AF102009_1|; |6318401|gb|AAF06877.1|AF102008_1|;|325278|gb|AAA43768.1|; |2463656|gb|AAB72043.1|;|18140834|gb|AAL60440.1|AF398871_1|;|18140822|gb|AAL60434.1|AF398865_1|; |9437960|gb|AAF87505.1|AF250477_1|;|324940|gb|AAA43631.1|; |9049388|dbj|BAA99402.1|;|71084265|gb|AAZ23578.1|; |71084263|gb|AAZ23577.1|;|71084261|gb|AAZ23576.1|; |71084259|gb|AAZ23575.1|;|71084257|gb|AAZ23574.1|; |71084255|gb|AAZ23573.1|;|71084253|gb|AAZ23572.1|; |71084251|gb|AAZ23571.1|;|73665386|gb|AAZ79400.1|; |55925912|gb|AAV68029.1|;|55925878|gb|AAV68012.1|; |55925862|gb|AAV68004.1|;|55925850|gb|AAV67998.1|; |55925834|gb|AAV67990.1|;|9802300|gb|AAF99677.1|AF258527_1|; |9802298|gb|AAF99676.1|AF258526_1|;|58374186|gb|AAW72229.1|; |29539584|gb|AAO88267.1|AF342823_1|;|37785460|gb|AAO46566.1|; |37785458|gb|AAO46565.1|;|37785456|gb|AAO46564.1|; |37785454|gb|AAO46563.1|;|37785452|gb|AAO46562.1|; |37785450|gb|AAO46561.1|;|37785448|gb|AAO46560.1|; |37785446|gb|AAO46559.1|;|37785444|gb|AAO46558.1|; |37785442|gb|AAO46557.1|;|37785440|gb|AAO46556.1|; |37785438|gb|AAO46555.1|;|37785436|gb|AAO46554.1|; |37785434|gb|AAO46553.1|;|37785044|gb|AAO46341.1|; |37785042|gb|AAO46340.1|;|37785040|gb|AAO46339.1|; |37785038|gb|AAO46338.1|;|37785036|gb|AAO46337.1|; |37785034|gb|AAO46336.1|;|37785032|gb|AAO46335.1|; |37785030|gb|AAO46334.1|;|37785028|gb|AAO46333.1|; |37785026|gb|AAO46332.1|;|37785024|gb|AAO46331.1|; |37785022|gb|AAO46330.1|;|37785020|gb|AAO46329.1|; |37785018|gb|AAO46328.1|;|37785016|gb|AAO46327.1|; |37785014|gb|AAO46326.1|;|37785012|gb|AAO46325.1|; |37785010|gb|AAO46324.1|;|3523119|gb|AAC34271.1|; |54126556|gb|AAV30842.1|;|52078177|gb|AAU25863.1|; |52078159|gb|AAU25853.1|;|52078141|gb|AAU25843.1|; |47834373|gb|AAT38884.1|;|54126513|gb|AAV30834.1|; |31442137|emb|CAD92258.1|;|30522957|gb|AAO65606.1|; |5732325|gb|AAD49038.1|AF156428_1|;|5732323|gb|AAD49037.1|AF156427_1|; |5732321|gb|AAD49036.1|AF156426_1|;|73912683|ref|YP_308851.1|; |18074831|emb|CAC84862.1|;|18074829|emb|CAC84861.1|; |18074827|emb|CAC84913.1|;|18074825|emb|CAC84912.1|; |18074823|emb|CAC84911.1|;|18074821|emb|CAC84910.1|; |18074819|emb|CAC84909.1|;|18074817|emb|CAC84908.1|; |77543697|gb|ABA87261.1|;|77543677|gb|ABA87250.1|; |77543657|gb|ABA87239.1|;|77543377|gb|ABA87099.1|; |77543356|gb|ABA87088.1|;|77543312|gb|ABA87065.1|; |77543256|gb|ABA87053.1|;|76786707|gb|ABA55039.1|; |76464433|gb|ABA43344.1|;|76454573|gb|ABA43208.1|; |76446442|gb|ABA43175.1|;|76446417|gb|ABA42997.1|; |76446398|gb|ABA42986.1|;|76446326|gb|ABA42947.1|; |76446307|gb|ABA42936.1|;|76443541|gb|ABA42583.1|; |76443522|gb|ABA42572.1|;|76443503|gb|ABA42561.1|; |76443484|gb|ABA42550.1|;|76443465|gb|ABA42539.1|; |76443446|gb|ABA42528.1|;|76443427|gb|ABA42517.1|; |76443408|gb|ABA42506.1|;|76443389|gb|ABA42495.1|; |76443370|gb|ABA42484.1|;|76443351|gb|ABA42473.1|; |76443332|gb|ABA42462.1|;|76443283|gb|ABA42451.1|; |76443264|gb|ABA42420.1|;|76443245|gb|ABA42409.1|; |76443226|gb|ABA42398.1|;|76443207|gb|ABA42387.1|; |76443188|gb|ABA42376.1|;|76441125|gb|ABA42365.1|; |76426762|gb|ABA42354.1|;|76418836|gb|ABA42343.1|; |764|1281|gb|ABA42332.1|;|76410537|gb|ABA42321.1|; |76403298|gb|ABA42310.1|;|7638|630|gb|ABA42299.1|; |76366083|gb|ABA42277.1|;|76366064|gb|ABA42266.1|; |76366045|gb|ABA42255.1|;|76366026|gb|ABA42244.1|; |75750359|gb|ABA26807.1|;|75750340|gb|ABA26796.1|; |75750321|gb|ABA26785.1|;|75750302|gb|ABA26774.1|; |75750283|gb|ABA26763.1|;|75750264|gb|ABA26752.1|; |75750245|gb|ABA26741.1|;|75750226|gb|ABA26730.1|; |75750207|gb|ABA26719.1|;|75750188|gb|ABA26708.1|; |72623485|gb|AAZ74625.1|;|75218844|gb|ABA18175.1|; |75217161|gb|ABA18164.1|;|75216235|gb|ABA18153.1|; |75215980|gb|ABA18142.1|;|75215317|gb|ABA18131.1|; |75214459|gb|ABA18120.1|;|75213056|gb|ABA18045.1|; |75206531|gb|ABA18034.1|;|75200787|gb|ABA16472.1|; |75181281|gb|ABA12792.1|;|75181143|gb|ABA12784.1|; |75180947|gb|ABA12770.1|;|75180861|gb|ABA12759.1|; |75180593|gb|ABA12748.1|;|75173041|gb|ABA12737.1|; |75171464|gb|ABA12726.1|;|75171319|gb|ABA12716.1|; |75168429|gb|ABA12704.1|;|74477300|gb|ABA08527.1|; |74477260|gb|ABA08505.1|;|74477241|gb|ABA08494.1|; 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|54299842|gb|AAV32644.1|;|13925398|gb|AAK49362.1|AF258826_1|;|13925395|gb|AAK49361.1|AF258825_1|;|13925392|gb|AAK49360.1|AF258824_1|;|13925389|gb|AAK49359.1|AF258821_1|;|13925386|gb|AAK49358.1|AF258820_1|;|13925383|gb|AAK49357.1|AF258819_1|;|13925380|gb|AAK49356.1|AF258818_1|;|13925377|gb|AAK49355.1|AF258817_1|;|13925374|gb|AAK49354.1|AF258816_1|; |47156561|gb|AAT12168.1|;|47156559|gb|AAT12167.1|; |47156557|gb|AAT12166.1|;|47156555|gb|AAT12165.1|; |47156553|gb|AAT12164.1|;|47156551|gb|AAT12163.1|; |47156549|gb|AAT12162.1|;|47156547|gb|AAT12161.1|; |47156545|gb|AAT12160.1|;|47156543|gb|AAT12159.1|; |47156541|gb|AAT12158.1|;|47156539|gb|AAT12157.1|; |47156537|gb|AAT12156.1|;|47156535|gb|AAT12155.1|; |47156533|gb|AAT12154.1|;|47156531|gb|AAT12153.1|; |47156529|gb|AAT12152.1|;|47156527|gb|AAT12151.1|; |47156525|gb|AAT12150.1|;|47156523|gb|AAT12149.1|; |47156521|gb|AAT12148.1|;|1430831|emb|CAA67498.1|; |19422189|gb|AAL87925.1|AF455727_1|;|19422183|gb|AAL87922.1|AF455724_1|;|19422181|gb|AAL87921.1|AF455723_1|; |14532423|gb|AAK64188.1|;|13661046|emb|CAC37002.1|; |5805279|gb|AAD51923.1|;|57916067|gb|AAW59406.1|; |57916013|gb|AAW59396.1|;|57915966|gb|AAW59388.1|; |47716769|gb|AAT37561.1|;|58531173|db|BAD89344.1|; |58531153|dbj|BAD89333.1|;|58531135|db|BAD89323.1|; |58531117|d|BAD89313.1|;|58531085|db|BAD89303.1|; |50956624|gb|AAT90830.1|;|50296498|gb|AAT73525.1|; |50296468|gb|AAT73510.1|;|50296462|gb|AAT73507.1|; |50296458|gb|AAT73505.1|;|50296456|gb|AAT73504.1|; |50296454|gb|AAT73503.1|;|50296452|gb|AAT73502.1|; |50296450|gb|AAT73501.1|;|50296448|gb|AAT73500.1|; |50296444|gb|AAT73498.1|;|50296440|gb|AAT73496.1|; |50296438|gb|AAT73495.1|;|50296436|gb|AAT73494.1|; |50296432|gb|AAT73492.1|;|50296430|gb|AAT73491.1|; |50296428|gb|AAT73490.1|;|50296416|gb|AAT73484.1|; |50296414|gb|AAT73483.1|;|50296412|gb|AAT73482.1|; |37963694|gb|AAR05984.1|;|37963692|gb|AAR05983.1|; |37963696|gb|AAR05985.1|;|38524562|dbj|BAD02360.1|; |38524542|dbj|BAD02349.1|;|24286097|gb|AAN46833.1|; |61612044|gb|AAX47280.1|;|61612038|gb|AAX47279.1|; |71000178|db|BAE07153.1|;|30025725|gb|AAP04506.1|; |70905275|gb|AAZ14161.1|;|70905273|gb|AAZ14160.1|; |70905271|gb|AAZ14159.1|;|70905269|gb|AAZ14158.1|; |70905267|gb|AAZ14157.1|;|70905265|gb|AAZ14156.1|; |70905263|gb|AAZ14155.1|;|70905261|gb|AAZ14154.1|; |70905259|gb|AAZ14153.1|;|70905257|gb|AAZ14152.1|; |70905255|gb|AAZ14151.1|;|70905253|gb|AAZ14150.1|; |3335435|gb|AAC32096.1|;|3335415|gb|AAC32085.1|; |56548870|gb|AAV97600.1|;|56548868|gb|AAV97599.1|; |56548866|gb|AAV97598.1|;|56548864|gb|AAV97597.1|; |56424948|gb|AAV91207.1|;|56424946|gb|AAV91206.1|; |56424942|gb|AAV91204.1|;|50542650|gb|AAT78590.1|; |50365727|gb|AAT76165.1|;|47834828|gb|AAT39049.1|; |47834824|gb|AAT39047.1|;|47834822|gb|AAT39046.1|; |47834814|gb|AAT39042.1|;|47834812|gb|AAT39041.1|; |40732896|emb|CAF04464.1|;|14275693|emb|CAC40038.1|; |13383273|dbj|BAB39508.1|;|13383271|dbj|BAB39507.1|; |13661044|emb|CAC37001.1|;|28823019|gb|AAO46889.1|; |28822828|gb|AAO46888.1|;|28822609|gb|AAO46887.1|; |28822076|gb|AAO46886.1|;|28821871|gb|AAO46888.1|; |28821644|gb|AAO46884.1|;|28821462|gb|AAO46883.1|; |28821280|gb|AAO46882.1|;|28821223|gb|AAO46881.1|; |27462113|gb|AAO15325.1|AF225521_1|;|27462111|gb|AAO15324.1|AF225520_1|;|27462109|gb|AAO15323.1|AF225519_1|;|27462107|gb|AAO15322.1|AF225518_1|;|21359664|gb|AAM49557.1|AF468839_1|; |20068025|emb|CAC84758.1|;|20068023|emb|CAC84686.1|; |20068021|emb|CAC84787.1|;|20068019|emb|CAC84786.1|; |20068017|emb|CAC84788.1|;|20068015|emb|CAC84784.1|; |20068007|emb|CAC84780.1|;|19697848|gb|AAL31428.1|; |19697846|gb|AAL31424.1|;|19697836|gb|AAL31419.1|; |19422195|gb|AAL87928.1|AF455730_1|;|19422193|gb|AAL87927.1|AF455729_1|;|19422191|gb|AAL87926.1|AF455728_1|;|19422187|gb|AAL87924.1|AF455726_1|;|19422185|gb|AAL87923.1|AF455728_1|;|16076717|gb|AAL14089.1|AF222819_1|;|16076715|gb|AAL14088.1|AF222818_1|; |13661048|emb|CAC37003.1|;|8482850|gb|AAF75122.1|AF115293_1|; |8452848|gb|AAF75121.1|AF115292_1|;|323669|gb|AAA42968.1|; |133517|sp|P16508|RRP1_IAMAN|;|133523|sp|P03430|RRP1_IAWI1|; |2806782|sp|P16506|RRP1_IAKOR|;|133527|sp|P16512|RRP1_IAZTF|; |1 33526|sp|P16510|RRP1_IAZON|;|133525|sp|P16509|RRP1_IAZH3|; |133524|sp|P16514|RRP1_IAWIS|;|133522|sp|P16513|RRP1_IATKM|; |1133521|sp|P16511|RRP1_IASIN|;|133518|sp|P16507|RRP1_IAME8|; |133512|sp|P18882|RRP1_IAKIE|;|133511|sp|P16505|RRP1_IAHTE|; |133510|sp|P16504|RRP1_IAHLO|;|133509|sp|P16503|RRP1_IAGU2|; |133506|sp|P16502|RRP1_IABE1|;|8647779|sp|Q82571|RRP1_IAFOM|; |6647775|sp|O91741|RRP1_IAKIT|;|8647773|sp|O89749|RRP1_IACKH|; |133531|sp|P19703|RRP1_INCJJ|;|133520|sp|P03431|RRP1_IAPUE|; |133519|sp|P03432|RRP1_IANT6|;|133505|sp|P21426|RRP1_IAANN|; |401026|sp|P31341|RRP1_IAV17|;|133516|sp|P26121|RRP1_IALE3|; |133515|sp|P26120|RRP1_IALE2|;|133514|sp|P26119|RRP1_IALE1|; |133508|sp|P26118|RRP1_IADUN|;|34733402|gb|AAQ81638.1|; |34733400|gb|AAQ81637.1|;|9863938|gb|AAG01228.1|AF216740_1|; |9863920|gb|AAG01218.1|AF216732_1|;|9863902|gb|AAG01208.1|AF216724_1|; |9863883|gb|AAG01198.1|AF216716_1|;|324980|gb|AAA43647.1|; |324970|gb|AAA43646.1

The preferred influenza strains referred to in the present invention,for example against which the present polypeptides should beimmunogenic, are those containing these specific proteins. The aboveaccession numbers specify explicitly the identity of the strain inaddition to the specific protein sequence.

In some preferred embodiments the polypeptide according to the presentinvention may comprise one or more sequences as described above andhaving at least 60% homology with a consensus sequence over known humanand avian influenza virus strains (or two or more epitopes of 7 aminoacids or more having at least 60% homology with such a sequence). Infurther preferred embodiments the polypeptide may comprise one or moresequences as described above and having at least 60% homology with aconsensus sequence over known human influenza virus strains (or two ormore epitopes of 7 amino acids or more having at least 60% homology withsuch a sequence).

The percent homology of a first polypeptide sequence to a secondpolypeptide sequence, as referred to in the context of the presentinvention, is defined as the number of amino acid residues in the secondsequence that match in both position and identity to those in the firstsequence, divided by the total number of amino acid residues in thesecond polypeptide (both first and second polypeptides must have thesame number of amino acid residues) and multiplied by 100. In thepresent invention, it is preferred that the polypeptide homology to thedefined sequences is 75% or more, 85% or more, 95% or more or 100% (orsubstantially 100%).

The epitopes within the sequences defined above are not especiallylimited, provided that they contain 7 amino acid residues or more.Preferably the epitopes are of a length that is appropriate for CTLepitopes in a particular vertebrate species, such as in a human, havinga specific MHC. Typically the epitopes contain 8, 9, 10, or 11 aminoacid residues, but may contain more if desired. Generally an appropriateepitope is one which is a CTL epitope in a vertebrate such as a human.

Typically, the polypeptide comprises between 7 and 100 amino acids, andpreferably from 8-50 amino acids. The size should not be so great thatuseful epitopes suffer from competition with non-protective epitopes inthe immune system (for this reason full proteins are not included), norshould the size be so small that only a very narrow range of protectionis offered. More preferred ranges are from 8-40 amino acids, 15-40 aminoacids and 15-35 amino acids. The most preferred length is from 20-35amino acid residues. It is particularly preferred that the polypeptideconsists of (or substantially consists of) a sequence selected from thesequences at the positions defined above in the specific list ofproteins set out above.

In addition to the polypeptides described above, which should not belarger than 100 amino acid residues in length, the invention alsoprovides multi-epitope immunogenic polypeptides comprising two or morepolypeptides of the present invention. These multi-epitope polypeptidesare not limited in size. Thus, they extend not only to the polypeptideshaving from 7-100 amino acid residues as outlined above, but also tolarger polypeptides, provided that these larger polypeptides comprisetwo or more units, each unit consisting of a polypeptide of theinvention. Thus, a polypeptide having 100 repeating units of a 7-meraccording to the present invention is encompassed by the presentinvention, as is a polypeptide having, say 52 units of one 8-merepitope, and 23 units of a second 10-mer epitope. Polypeptides of thistype will not suffer from the competition problems associated withsimilar length polypeptides that comprise only one or two epitopes. Forthe avoidance of doubt, the multi-epitope polypeptide may comprisemultiple copies of the same epitope, or single copies of a plurality ofdifferent epitopes, or multiple copies of 2 or more epitopes.

Also provided by the invention is a polypeptide composition comprisingtwo or more different polypeptides as defined above. Thus, thepolypeptide composition may comprise any number of polypeptides of thepresent invention together in the same mixture or formulation. Thepresence of a plurality of polypeptides together is useful since eachmay elicit its own immune response, widening the protective effect ofthe composition. It is particularly preferred that the compositioncontains all of the sequences of SEQ ID 1-6 either each in a separatepeptide or several in a smaller number of peptides (e.g. 3 combined inone larger peptide and the other three 3 in another larger peptide,etc.).

The invention also provides a polypeptide construct, which constructcomprises a polypeptide as defined above and a carrier. The constructmay be formed by combining two or more epitopes and/or a polypeptide asdefined above with the carrier. The carrier may be a molecule, such asan adjuvant and/or an excipient. Combining in this context means eithermixing together, or attaching together (e.g. via a covalent linkage).

The present invention further provides a polypeptide as defined abovefor use in medicine. Also provided is a medicament or vaccinecomposition against influenza, comprising a polypeptide as definedabove, and one or more appropriate excipients and/or adjuvants, or apolypeptide construct as defined above and optionally one or moreappropriate excipients and/or adjuvants (if the carrier part of theconstruct is itself an excipient or adjuvant, then a further excipientor adjuvant may not be needed). The excipient or adjuvant is notespecially limited, and any excipients or adjuvants used in medicamentsand vaccines may be employed. The medicament or vaccine composition maybe produced according to any known method appropriately adapted to thepresent invention, such as by mixing a polypeptide of the invention withan appropriate excipient.

A method of producing a polypeptide as defined above is also provided bythe invention. The method is not especially limited, and typicallycomprises joining two or more epitopes to form the polypeptide. Thepolypeptide may, however, be synthesised by direct chemical synthesis(e.g. incorporating one amino acid at a time until the full polypeptideis formed) or by recombinant methods. Such general methods are wellknown to the skilled person and may be adapted to the present inventionas desired. In some instances, the polypeptide of the present inventionmay comprise additional amino acid sequences at one or both termini tohelp in synthesis of the polypeptide. These additional sequences arepreferably from 1-5 amino acids in length. Typically 3 amino acids areinvolved. For example, in one preferred embodiment, SEQ ID 6 comprisesthe amino acids AAS immediately prior to the IIG part of the sequence.

The invention still further provides use of a polypeptide or compositionas defined above, in the manufacture of a medicament or vaccine,effective in the treatment or prevention of influenza. Also provided isa method of treating or preventing influenza, which method comprisesadministering a polypeptide, a composition, a medicament or a vaccine asdefined above to a vertebrate. The method of administration is notespecially limited, and may comprise subcutaneous, intramuscuscular,intra-venous, intra-dermal, or intra-nasal administration, or may beadministered orally (e.g. in the form of a pill or a liquidpreparation), or may be in the form of a suppository, if desired. Theform of such administration preparations is not especially limited, andknown forms may be employed with appropriate modifications that will beapparent to the skilled person. The dosage is not especially limited andmay range from 1 μg to 100 g of the polypeptide per individual,depending upon the size, weight and species of the individual involved.

The invention may be applied to any vertebrate, since the immune systemsof vertebrates operate in a related manner. Typically, the vertebratereferred to in the present context is a mammal, bird, a reptile or afish. It is especially preferred that the vertebrate is a human, adomestic animal (such as a dog or a cat), a farm animal (such as a pigor a horse), a bovine animal (such as cattle, or a cow), or fowl (suchas a domestic bird, a farm bird, or a game bird). When the vertebrate isa bird, it is preferably a chicken, a turkey, a duck, or a goose.

Examples of human MHCs (HLAs) that may be employed with the presentinvention include the following:

HLA-A

A*010101, A*010102, A*010103, A*0102, A*0103, A*0104N, A*0106, A*0107,A*0108, A*0109, A*0110, A*02010101, A*02010102L, A*020102, A*020103,A*020104, A*020105, A*020106, A*020107, A*020108, A*020109, A*020110,A*020111, A*0202, A*020301, A*020302, A*0204, A*0205, A*020601,A*020602, A*020603, A*0207, A*0208, A*0209, A*0210, A*0211, A*0212,A*0213, A*0214, A*0215N, A*0216, A*021701, A*021702, A*0218, A*0219,A*022001, A*022002, A*0221, A*0222, A*0224, A*0225, A*0226, A*0227,A*0228, A*0229, A*0230, A*0231, A*0232N, A*0233, A*0234, A*023501,A*023502, A*0236, A*0237, A*0238, A*0239, A*0240, A*0241, A*0242,A*0243N, A*0244, A*0245, A*0246, A*0247, A*0248, A*0249, A*0250, A*0251,A*0252, A*0253N, A*0254, A*0255, A*0256, A*0257, A*0258, A*0259, A*0260,A*0261, A*0262, A*0263, A*0264, A*0265, A*0266, A*0267, A*0268, A*0269,A*0270, A*0271, A*0272, A*0273, A*03010101, A*03010102N, A*03010103,A*030102, A*030103, A*0302, A*0303N, A*0304, A*0305, A*0306, A*0307,A*0308, A*0309, A*0310, A*0311N, A*0312, A*0313, A*0314, A*110101,A*110102, A*1102, A*1103, A*1104, A*1105, A*1106, A*1107, A*1108,A*1109, A*1110, A*1111, A*1112, A*1113, A*1114, A*1115, A*1116, A*1117,A*1118, A*119, A*2301, A*2302, A*2303, A*2304, A*2305, A*2306, A*2307N,A*2308N, A*2309, A*2310, A*2311N, A*2312, A*24020101, A*24020102L,A*240202, A*240203, A*240204, A*240205, A*240206, A*240301, A*240302,A*2404, A*2405, A*2406, A*2407, A*2408, A*2409N, A*2410, A*2411N,A*2413, A*2414, A*2415, A*2417, A*2418, A*2419, A*2420, A*2421, A*2422,A*2423, A*2424, A*2425, A*2426, A*2427, A*2428, A*2429, A*2430, A*2431,A*2432, A*2433, A*2434, A*2435, A*2436N, A*2437, A*2438, A*2439,A*2440N, A*2441, A*2442, A*2443, A*2444, A*2445N, A*2446, A*250101,A*250102, A*2502, A*2503, A*2504, A*2601, A*2602, A*2603, A*2604,A*2605, A*2606, A*260701, A*260702, A*2608, A*2609, A*2610, A*2611N,A*2612, A*2613, A*2614, A*2615, A*2616, A*2617, A*2618, A*2619, A*2620,A*2621, A*2622, A*2623, A*29010101, A*29010102N, A*290201, A*290202,A*290203, A*2903, A*2904, A*2905, A*2906, A*2907, A*2908N, A*2909,A*2910, A*2911, A*300101, A*300102, A*300201, A*300202, A*3003, A*3004,A*3006, A*3007, A*3008, A*3009, A*3010, A*3011, A*3012, A*310102,A*3102, A*3103, A*3104, A*3105, A*3106, A*3107, A*3108, A*3109, A*3110,A*3201, A*3202, A*3203, A*3204, A*3205, A*3206, A*3207, A*3208, A*3301,A*330301, A*330302, A*3304, A*3305, A*3306, A*3307, A*3401, A*3402,A*3403, A*3404, A*3405, A*3406, A*3601, A*3602, A*3603, A*3604, A*4301,A*6601, A*6602, A*6603, A*6604, A*680101, A*680102, A*680103, A*6802,A*680301, A*680302, A*6804, A*6805, A*6806, A*6807, A*6808, A*6809,A*6810, A*6811N, A*6812, A*6813, A*6814, A*6815, A*6816, A*6817,A*6818N, A*6819, A*6820, A*6821, A*6822, A*6823, A*6824, A*6825, A*6826,A*6827, A*6901, A*7401, A*7402, A*7403, A*7404, A*7405, A*7406, A*7407,A*7408, A*7409, A*7410, A*8001.

HLA-B

B*070201, B*070202, B*070203, B*070204, B*0703, B*0704, B*0705, B*0706,B*0707, B*0708, B*0709, B*0710, B*0711, B*0712, B*0713, B*0714, B*0715,B*0716, B*0717, B*0718, B*0719, B*0720, B*0721, B*0722, B*0723, B*0724,B*0725, B*0726, B*0727, B*0728, B*0729, B*0730, B*0731, B*0732, B*0733,B*0734, B*0735, B*0736, B*0737, B*0738, B*0801, B*0802, B*0803, B*0804,B*0805, B*0806, B*0807, B*0808N, B*0809, B*0810, B*0811, B*0812, B*0813,B*0814, B*0815, B*0816, B*0817, B*0818, B*0819N, B*0820, B*0821, B*0822,B*1301, B*1302, B*1303, B*1304, B*1306, B*1307N, B*1308, B*1309, B*1310,B*1311, B*1312, B*1313, B*1401, B*1402, B*1403, B*1404, B*1405,B*140601, B*140602, B*15010101, B*15010102N, B*150102, B*150103,B*150104, B*150105, B*1502, B*1503, B*1504, B*1505, B*1506, B*1507,B*1508, B*1509, B*1510, B*151101, B*151102, B*1512, B*1513, B*1514,B*1515, B*1516, B*15170101, B*15170102, B*1518, B*1519, B*1520, B*1521,B*1523, B*1524, B*1525, B*1526N, B*1527, B*1528, B*1529, B*1530, B*1531,B*1532, B*1533, B*1534, B*1535, B*1536, B*1537, B*1538, B*1539, B*1540,B*1542, B*1543, B*1544, B*1545, B*1546, B*1547, B*1548, B*1549, B*1550,B*1551, B*1552, B*1553, B*1554, B*1555, B*1556, B*1557, B*1558, B*1560,B*1561, B*1562, B*1563, B*1564, B*1565, B*1566, B*1567, B*1568, B*1569,B*1570, B*1571, B*1572, B*1573, B*1574, B*1575, B*1576, B*1577, B*1578,B*1579N, B*1580, B*1581, B*1582, B*1583, B*1584, B*1585, B*1586, B*1587,B*1588, B*1589, B*1590, B*1591, B*1592, B*1593, B*1594N, B*180101,B*180102, B*1802, B*1803, B*1804, B*1805, B*1806, B*1807, B*1808,B*1809, B*1810, B*1811, B*1812, B*1813, B*1814, B*1815, B*1817N, B*1818,B*1819, B*1820, B*2701, B*2702, B*2703, B*2704, B*270502, B*270503,B*270504, B*270505, B*270506, B*270507, B*2706, B*2707, B*2708, B*2709,B*2710, B*2711, B*2712, B*2713, B*2714, B*2715, B*2716, B*2717, B*2718,B*2719, B*2720, B*2721, B*2723, B*2724, B*2725, B*2726, B*350101,B*350102, B*3502, B*3503, B*3504, B*3505, B*3506, B*3507, B*3508,B*350901, B*350902, B*3510, B*3511, B*3512, B*3513, B*351401, B*351402,B*3515, B*3516, B*3517, B*3518, B*3519, B*3520, B*3521, B*3522, B*3523,B*3524, B*3525, B*3526, B*3527, B*3528, B*3529, B*3530, B*3531, B*3532,B*3533, B*3534, B*3535, B*3536, B*3537, B*3538, B*3539, B*3540N, B*3541,B*3542, B*3543, B*3544, B*3545, B*3546, B*3547, B*3548, B*3549, B*3550,B*3551, B*3552, B*3553N, B*3701, B*3702, B*3703N, B*3704, B*3705,B*3706, B*3707, B*3801, B*380201, B*380202, B*3803, B*3804, B*3805,B*3806, B*3807, B*3808, B*3809, B*3810, B*390101, B*390103, B*390104,B*390201, B*390202, B*3903, B*3904, B*3905, B*390601, B*390602, B*3907,B*3908, B*3909, B*3910, B*3911, B*3912, B*3913, B*3914, B*3915, B*3916,B*3917, B*3918, B*3919, B*3920, B*3922, B*3923, B*3924, B*3925N, B*3926,B*3927, B*3928, B*3929, B*3930, B*3931, B*3932, B*400101, B*400102,B*400103, B*400104, B*400105, B*400201, B*400202, B*4003, B*4004,B*4005, B*40060101, B*40060102, B*4007, B*4008, B*4009, B*4010, B*4011,B*4012, B*4013, B*401401, B*401402, B*401403, B*4015, B*4016, B*4018,B*4019, B*4020, B*4021, B*4022N, B*4023, B*4024, B*4025, B*4026, B*4027,B*4028, B*4029, B*4030, B*4031, B*4032, B*4033, B*4034, B*4035, B*4036,B*4037, B*4038, B*4039, B*4040, B*4042, B*4043, B*4044, B*4045, B*4046,B*4047, B*4048, B*4049, B*4050, B*4051, B*4052, B*4053, B*4054, B*4055,B*4056, B*4057, B*4101, B*4102, B*4103, B*4104, B*4105, B*4106, B*4201,B*4202, B*4204, B*420501, B*420502, B*4206, B*44020101, B*440201025,B*440202, B*440203, B*440301, B*440302, B*4404, B*4405, B*4406, B*4407,B*4408, B*4409, B*4410, B*4411, B*4412, B*4413, B*4414, B*4415, B*4416,B*4417, B*4418, B*4419N, B*4420, B*4421, B*4422, B*4423N, B*4424,B*4425, B*4426, B*4427, B*4428, B*4429, B*4430, B*4431, B*4432, B*4433,B*4434, B*4435, B*4436, B*4437, B*4438, B*4439, B*4440, B*4501, B*4502,B*4503, B*4504, B*4505, B*4506, B*4507, B*4601, B*4602, B*4603, B*4604,B*47010101, B*47010102, B*4702, B*4703, B*4704, B*4705, B*4801, B*4802,B*4803, B*4804, B*4805, B*4806, B*4807, B*4808, B*4809, B*4810, B*4901,B*4902, B*4903, B*5001, B*5002, B*5004, B*510101, B*510102, B*510103,B*510104, B*510105, B*510201, B*510202, B*5103, B*5104, B*5105, B*5106,B*5107, B*5108, B*5109, B*5110, B*5111N, B*5112, B*511301, B*511302,B*5114, B*5115, B*5116, B*5117, B*5118, B*5119, B*5120, B*5121, B*5122,B*5123, B*5124, B*5126, B*5127N, B*5128, B*5129, B*5130, B*5131, B*5132,B*5133, B*5134, B*5135, B*5136, B*520101, B*520102, B*520103, B*520104,B*5202, B*5203, B*5204, B*5205, B*5206, B*530101, B*530102, B*5302,B*5303, B*5304, B*5305, B*5306, B*5307, B*5308, B*5309, B*5401, B*5402,B*5501, B*5502, B*5503, B*5504, B*5505, B*5507, B*5508, B*5509, B*5510,B*5511, B*5512, B*5513, B*5514, B*5515, B*5516, B*5601, B*5602, B*5603,B*5604, B*560501, B*560502, B*5606, B*5607, B*5608, B*5609, B*5610,B*5611, B*5612, B*5613, B*5614, B*570101, B*570102, B*5702, B*570301,B*570302, B*5704, B*5705, B*5706, B*5707, B*5708, B*5709, B*5801,B*5802, B*5804, B*5805, B*5806, B*5807, B*5808, B*5809, B*5810N, B*5901,B*670101, B*670102, B*6702, B*7301, B*7801, B*780201, B*780202, B*7803,B*7804, B*7805, B*8101, B*8102, B*8201, B*8202, B*8301.

HLA-C

Cw*010201, Cw*010202, Cw*0103, Cw*0104, Cw*0105, Cw*0106, Cw*0107,Cw*0108, Cw*0109, Cw*0110, Cw*020201, Cw*020202, Cw*020203, Cw*020204,Cw*020205, Cw*0203, Cw*0204, Cw*0205, Cw*0206, Cw*0207, Cw*0208,Cw*0209, Cw*030201, Cw*030202, Cw*030301, Cw*030302, Cw*030303,Cw*030304, Cw*030401, Cw*030402, Cw*030403, Cw*0305, Cw*0306, Cw*0307,Cw*0308, Cw*0309, Cw*0310, Cw*0311, Cw*0312, Cw*0313, Cw*0314, Cw*0315,Cw*0316, Cw*0317, Cw*0318, Cw*04010101, Cw*04010102, Cw*040102, Cw*0403,Cw*040401, Cw*040402, Cw*0405, Cw*0406, Cw*0407, Cw*0408, Cw*0409N,Cw*0410, Cw*0411, Cw*0412, Cw*0413, Cw*0414, Cw*0415, Cw*050101,Cw*050102, Cw*0502, Cw*0503, Cw*0504, Cw*0505, Cw*0506, Cw*0507N,Cw*0508, Cw*0509, Cw*0510, Cw*0602, Cw*0603, Cw*0604, Cw*0605, Cw*0606,Cw*0607, Cw*0608, Cw*0609, Cw*0610, Cw*0611, Cw*070101, Cw*070102,Cw*070103, Cw*07020101, Cw*07020102, Cw*07020103, Cw*0703, Cw*070401,Cw*070402, Cw*0705, Cw*0706, Cw*0707, Cw*0708, Cw*0709, Cw*0710,Cw*0711, Cw*0712, Cw*0713, Cw*0714, Cw*0715, Cw*0716, Cw*0717, Cw*0718,Cw*0719, Cw*0720, Cw*0721, Cw*0722, Cw*0723, Cw*0724, Cw*0725, Cw*0726,Cw*0727, Cw*0728, Cw*0729, Cw*080101, Cw*080102, Cw*0802, Cw*0803,Cw*0804, Cw*0805, Cw*0806, Cw*0807, Cw*0808, Cw*0809, Cw*0810, Cw*0811,Cw*0812, Cw*120201, Cw*120202, Cw*120203, Cw*120301, Cw*120302,Cw*120303, Cw*120401, Cw*120402, Cw*1205, Cw*1206, Cw*1207, Cw*1208,Cw*1209, Cw*1210, Cw*1211, Cw*1212, Cw*1213, Cw*1214, Cw*1215,Cw*140201, Cw*140202, Cw*140203, Cw*1403, Cw*1404, Cw*1405, Cw*150201,Cw*150202, Cw*1503, Cw*1504, Cw*150501, Cw*150502, Cw*150503, Cw*150504,Cw*1506, Cw*1507, Cw*1508, Cw*1509, Cw*1510, Cw*1511, Cw*1512, Cw*1601,Cw*1602, Cw*160401, Cw*1606, Cw*1701, Cw*1702, Cw*1703, Cw*1801,Cw*1802.

HLA-E

E*0101, E*010301, E*010302, E*010303, E*0104.

HLA-F

F*010101, F*010102.

HLA-G

G*010101, G*010102, G*010103, G*010104, G*010105, G*010106, G*010107,G*010108, G*0102, G*0103, G*010401, G*010402, G*010403, G*0105N, G*0106.

HLA-DRA

DRA*0101, DRA*010201, DRA*010202.

HLA-DRB1

DRB1*010101, DRB1*010102, DRB1*010103, DRB1*010201, DRB1*010202,DRB1*010203, DRB1*010204, DRB1*0103, DRB1*0104, DRB1*0105, DRB1*0106,DRB1*0107, DRB1*0108, DRB1*0109, DRB1*0110, DRB1*0111, DRB1*030101,DRB1*030102, DRB1*030201, DRB1*030202, DRB1*0303, DRB1*0304,DRB1*030501, DRB1*030502, DRB1*0306, DRB1*0307, DRB1*0308, DRB1*0309,DRB1*0310, DRB1*0311, DRB1*0312, DRB1*0313, DRB1*0314, DRB1*0315,DRB1*0316, DRB1*0317, DRB1*0318, DRB1*0319, DRB1*0320, DRB1*0321,DRB1*0322, DRB1*0323, DRB1*0324, DRB1*0325, DRB1*0326, DRB1*0327,DRB1*0328, DRB1*040101, DRB1*040102, DRB1*0402, DRB1*040301,DRB1*040302, DRB1*0404, DRB1*040501, DRB1*040502, DRB1*040503,DRB1*040504, DRB1*0406, DRB1*040701, DRB1*040702, DRB1*040703,DRB1*0408, DRB1*0409, DRB1*0410, DRB1*0411, DRB1*0412, DRB1*0413,DRB1*0414, DRB1*0415, DRB1*0416, DRB1*0417, DRB1*0418, DRB1*0419,DRB1*0420, DRB1*0421, DRB1*0422, DRB1*0423, DRB1*0424, DRB1*0425,DRB1*0426, DRB1*0427, DRB1*0428, DRB1*0429, DRB1*0430, DRB1*0431,DRB1*0432, DRB1*0433, DRB1*0434, DRB1*0435, DRB1*0436, DRB1*0437,DRB1*0438, DRB1*0439, DRB1*0440, DRB1*0441, DRB1*0442, DRB1*0443,DRB1*0444, DRB1*0445, DRB1*0446, DRB1*0447, DRB1*0448, DRB1*0449,DRB1*0450, DRB1*070101, DRB1*070102, DRB1*0703, DRB1*0704, DRB1*0705,DRB1*0706, DRB1*0707, DRB1*0708, DRB1*080101, DRB1*080102, DRB1*080201,DRB1*080202, DRB1*080203, DRB1*080302, DRB1*080401, DRB1*080402,DRB1*080403, DRB1*080404, DRB1*0805, DRB1*0806, DRB1*0807, DRB1*0808,DRB1*0809, DRB1*0810, DRB1*0811, DRB1*0812, DRB1*0813, DRB1*0814,DRB1*0815, DRB1*0816, DRB1*0817, DRB1*0818, DRB1*0819, DRB1*0820,DRB1*0821, DRB1*0822, DRB1*0823, DRB1*0824, DRB1*0825, DRB1*0826,DRB1*0827, DRB1*0828, DRB1*0829, DRB1*090102, DRB1*090103, DRB1*0902,DRB1*0903, DRB1*100101, DRB1*100102, DRB1*110101, DRB1*110102,DRB1*110103, DRB1*110104, DRB1*110105, DRB1*1102, DRB1*1103,DRB1*110401, DRB1*110402, DRB1*1105, DRB1*110601, DRB1*110602,DRB1*1107, DRB1*110801, DRB1*110802, DRB1*1109, DRB1*1110, DRB1*1111,DRB1*111201, DRB1*111202, DRB1*1113, DRB1*1114, DRB1*1115, DRB1*1116,DRB1*1117, DRB1*1118, DRB1*1119, DRB1*1120, DRB1*1121, DRB1*1122,DRB1*1123, DRB1*1124, DRB1*1125, DRB1*1126, DRB1*112701, DRB1*112702,DRB1*1128, DRB1*1129, DRB1*1130, DRB1*1131, DRB1*1132, DRB1*1133,DRB1*1134, DRB1*1135, DRB1*1136, DRB1*1137, DRB1*1138, DRB1*1139,DRB1*1140, DRB1*1141, DRB1*1142, DRB1*1143, DRB1*1144, DRB1*1145,DRB1*1146, DRB1*1147, DRB1*1148, DRB1*1149, DRB1*1150, DRB1*1151,DRB1*1152, DRB1*1153, DRB1*1154, DRB1*120101, DRB1*120102, DRB1*120201,DRB1*120202, DRB1*120302, DRB1*1204, DRB1*1205, DRB1*1206, DRB1*1207,DRB1*1208, DRB1*1209, DRB1*1210, DRB1*130101, DRB1*130102, DRB1*130103,DRB1*130201, DRB1*130202, DRB1*130301, DRB1*130302, DRB1*1304,DRB1*1305, DRB1*1306, DRB1*130701, DRB1*130702, DRB1*1308, DRB1*1309,DRB1*1310, DRB1*1311, DRB1*1312, DRB1*1313, DRB1*131401, DRB1*131402,DRB1*1315, DRB1*1316, DRB1*1317, DRB1*1318, DRB1*1319, DRB1*1320,DRB1*1321, DRB1*1322, DRB1*1323, DRB1*1324, DRB1*1325, DRB1*1326,DRB1*1327, DRB1*1328, DRB1*1329, DRB1*1330, DRB1*1331, DRB1*1332,DRB1*1333, DRB1*1334, DRB1*1335, DRB1*1336, DRB1*1337, DRB1*1338,DRB1*1339, DRB1*1340, DRB1*1341, DRB1*1342, DRB1*1343, DRB1*1344,DRB1*1345, DRB1*1346, DRB1*1347, DRB1*1348, DRB1*1349, DRB1*1350,DRB1*1351, DRB1*1352, DRB1*1353, DRB1*1354, DRB1*1355, DRB1*1356,DRB1*1357, DRB1*1358, DRB1*1359, DRB1*1360, DRB1*1361, DRB1*1362,DRB1*1363, DRB1*1364, DRB1*1365, DRB1*140101, DRB1*140102, DRB1*1402,DRB1*140301, DRB1*140302, DRB1*1404, DRB1*140501, DRB1*140502,DRB1*1406, DRB1*140701, DRB1*140702, DRB1*1408, DRB1*1409, DRB1*1410,DRB1*1411, DRB1*1412, DRB1*1413, DRB1*1414, DRB1*1415, DRB1*1416,DRB1*1417, DRB1*1418, DRB1*1419, DRB1*1420, DRB1*1421, DRB1*1422,DRB1*1423, DRB1*1424, DRB1*1425, DRB1*1426, DRB1*1427, DRB1*1428,DRB1*1429, DRB1*1430, DRB1*1431, DRB1*1432, DRB1*1433, DRB1*1434,DRB1*1435, DRB1*1436, DRB1*1437, DRB1*1438, DRB1*1439, DRB1*1440,DRB1*1441, DRB1*1442, DRB1*1443, DRB1*1444, DRB1*1445, DRB1*1446,DRB1*1447, DRB1*1448, DRB1*150101, DRB1*150102, DRB1*150103,DRB1*150104, DRB1*150105, DRB1*150201, DRB1*150202, DRB1*150203,DRB1*1503, DRB1*1504, DRB1*1505, DRB1*1506, DRB1*1507, DRB1*1508,DRB1*1509, DRB1*1510, DRB1*1511, DRB1*1512, DRB1*1513, DRB1*1514,DRB1*1515, DRB1*1516, DRB1*160101, DRB1*160102, DRB1*160201,DRB1*160202, DRB1*1603, DRB1*1604, DRB1*160501, DRB1*160502, DRB1*1607,DRB1*1608.

HLA-DRB2-9

DRB2*0101, DRB3*010101, DRB3*01010201, DRB3*01010202, DRB3*010103,DRB3*010104, DRB3*0102, DRB3*0103, DRB3*0104, DRB3*0105, DRB3*0106,DRB3*0107, DRB3*0108, DRB3*0109, DRB3*0110, DRB3*0111, DRB3*0201,DRB3*020201, DRB3*020202, DRB3*020203, DRB3*020204, DRB3*0203,DRB3*0204, DRB3*0205, DRB3*0206, DRB3*0207, DRB3*0208, DRB3*0209,DRB3*0210, DRB3*0211, DRB3*0212, DRB3*0213, DRB3*0214, DRB3*0215,DRB3*0216, DRB3*0217, DRB3*0218, DRB3*0219, DRB3*030101, DRB3*030102,DRB3*0302, DRB3*0303, DRB4*01010101, DRB4*0102, DRB4*01030101,DRB4*01030102N, DRB4*010302, DRB4*010303, DRB4*010304, DRB4*0104,DRB4*0105, DRB4*0106, DRB4*0107, DRB4*0201N, DRB4*0301N, DRB5*010101,DRB5*010102, DRB5*0102, DRB5*0103, DRB5*0104, DRB5*0105, DRB5*0106,DRB5*0107, DRB5*0108N, DRB5*0109, DRB5*0110N, DRB5*0111, DRB5*0112,DRB5*0113, DRB5*0202, DRB5*0203, DRB5*0204, DRB5*0205, DRB6*0101,DRB6*0201, DRB6*0202, DRB7*010101, DRB7*010102, DRB8*0101, DRB9*0101.

HLA-DQA1

DQA1*010101, DQA1*010102, DQA1*010201, DQA1*010202, DQA1*0103,DQA1*010401, DQA1*010402, DQA1*0105, DQA1*0106, DQA1*0107, DQA1*0201,DQA1*030101, DQA1*0302, DQA1*0303, DQA1*040101, DQA1*040102, DQA1*0402,DQA1*0403N, DQA1*0404, DQA1*050101, DQA1*050102, DQA1*0502, DQA1*0503,DQA1*0504, DQA1*0505, DQA1*060101, DQA1*060102, DQA1*0602.

HLA-DQB1

DQB1*020101, DQB1*020102, DQB1*0202, DQB1*0203, DQB1*030101,DQB1*030102, DQB1*030201, DQB1*030202, DQB1*030302, DQB1*030303,DQB1*0304, DQB1*030501, DQB1*030502, DQB1*030503, DQB1*0306, DQB1*0307,DQB1*0308, DQB1*0309, DQB1*0310, DQB1*0311, DQB1*0312, DQB1*0313,DQB1*0401, DQB1*0402, DQB1*050101, DQB1*050102, DQB1*050201,DQB1*050202, DQB1*050301, DQB1*050302, DQB1*0504, DQB1*060101,DQB1*060102, DQB1*060103, DQB1*0602, DQB1*0603, DQB1*060401,DQB1*060402, DQB1*060501, DQB1*060502, DQB1*0606, DQB1*0607, DQB1*0608,DQB1*0609, DQB1*0610, DQB1*061101, DQB1*061102, DQB1*0612, DQB1*0613,DQB1*0614, DQB1*0615, DQB1*0616, DQB1*0617, DQB1*0618, DQB1*0619,DQB1*0620, DQB1*0621, DQB1*0622, DQB1*0623.

HLA-DPA1

DPA1*010301, DPA1*010302, DPA1*010303, DPA1*0104, DPA1*0105, DPA1*0106,DPA1*0107, DPA1*0108, DPA1*020101, DPA1*020102, DPA1*020103,DPA1*020104, DPA1*020105, DPA1*020106, DPA1*020201, DPA1*020202,DPA1*020203, DPA1*0203, DPA1*0301, DPA1*0302, DPA1*0303, DPA1*0401.

HLA-DPB1

DPB1*010101, DPB1*010102, DPB1*010103, DPB1*0102, DPB1*020102,DPB1*020103, DPB1*020104, DPB1*020105, DPB1*020106, DPB1*0202,DPB1*0203, DPB1*030101, DPB1*030102, DPB1*0302, DPB1*040101,DPB1*040102, DPB1*0402, DPB1*0501, DPB1*0601, DPB1*0801, DPB1*0901,DPB1*1001, DPB1*110101, DPB1*110102, DPB1*1301, DPB1*1401, DPB1*1501,DPB1*1601, DPB1*1701, DPB1*1801, DPB1*1901, DPB1*200101, DPB1*200102,DPB1*2101, DPB1*2201, DPB1*2301, DPB1*2401, DPB1*2501, DPB1*260101,DPB1*260102, DPB1*2701, DPB1*2801, DPB1*2901, DPB1*3001, DPB1*3101,DPB1*3201, DPB1*3301, DPB1*3401, DPB1*3501, DPB1*3601, DPB1*3701,DPB1*3801, DPB1*3901, DPB1*4001, DPB1*4101, DPB1*4401, DPB1*4501,DPB1*4601, DPB1*4701, DPB1*4801, DPB1*4901, DPB1*5001, DPB1*5101,DPB1*5201, DPB1*5301, DPB1*5401, DPB1*5501, DPB1*5601, DPB1*5701,DPB1*5801, DPB1*5901, DPB1*6001, DPB1*6101N, DPB1*6201, DPB1*6301,DPB1*6401N, DPB1*6501, DPB1*6601, DPB1*6701, DPB1*6801, DPB1*6901,DPB1*7001, DPB1*7101, DPB1*7201, DPB1*7301, DPB1*7401, DPB1*7501,DPB1*7601, DPB1*7701, DPB1*7801, DPB1*7901, DPB1*8001, DPB1*8101,DPB1*8201, DPB1*8301, DPB1*8401, DPB1*8501, DPB1*8601, DPB1*8701,DPB1*8801, DPB1*8901, DPB1*9001, DPB1*9101, DPB1*9201, DPB1*9301,DPB1*9401, DPB1*9501, DPB1*9601, DPB1*9701, DPB1*9801, DPB1*9901.

HLA-DMA

DMA*0101, DMA*0102, DMA*0103, DMA*0104.

HLA-DMB

DMB*0101, DMB*0102, DMB*0103, DMB*0104, DMB*0105, DMB*0106.

HLA-DOA

DOA*010101, DOA*01010201, DOA*01010202, DOA*01010203, DOA*010103,DOA*01010401, DOA*01010402, DOA*010105.

HLA-DOB

DOB*01010101, DOB*01010102, DOB*010102, DOB*010201, DOB*010202,DOB*0103, DOB*01040101, DOB*01040102.

MHC Class I

H-2 Db, H-2Dd, H-2Dk, H-2Dq, H-2 Kb, H-2 Kd, H-2Kk, H-2Ld, H-2M3, H-2Ad,H-2Ag7, H-2Ak, H2-Ab, H-2Ed, H-2Ek, H-2Bxk, H-2F, H-21, H-2P, H-2R,H-2S, H-2Sxd, H-2T4, H-2U.

MHC Class II

I-Ab, I-Ad, I-Ag7, I-Ak, I-Ap, I-Aq, I—Ar, I—As, I-Au, I-Av, I-Ea, I-Eb,I-Ed, I-Ek, I—Es, I—Eu, H-2Q, H-2Qa-2, H-2Qa-2a, Qa-1a, Qa-1b.

The invention is not limited to such MHC and HLA molecules, and can beadapted to newly discovered such molecules, if desired, simply byestablishing the reactivity of substances such as peptides with themolecules. This can be readily achieved using known techniques that arestandard in the field. Particularly preferred HLA alleles for use withthe present invention include the following:

HLA Class I HLA A HLA B HLA Cw A*6802 B*5801 Cw*1701 A*6801 B*5701Cw*1601 A*6601 B*5501 Cw*1502 A*3303 B*5201 Cw*1402 A*3301 B*5101Cw*1203 A*3201 B*5001 Cw*0802 A*310102 B*4901 Cw*0801 A*3002 B*4501Cw*0704 A*3001 B*4403 Cw*0703 A*2902 B*4402 Cw*0702 A*2608 B*4101Cw*0701 A*2601 B*4002 Cw*0602 A*2501 B*4001 Cw*0501 A*2402 B*3901Cw*0401 A*2301 B*3801 Cw*0304 A*1101 B*3701 Cw*0303 A*0302 B*3503Cw*0202 A*0301 B*3501 Cw*0102 A*0205 B*2705 A*0201 B*1801 A*0101 B*1501B*1402 B*1401 B*1302 B*0801 B*0705 B*0702

HLA Class II HLA DPB HLA DQA HLA DQB HLA DRB DPB1*1701 DQA1*0505DQB1*0604 DRB1*1601 DPB1*1301 DQA1*0501 DQB1*0603 DRB1*1501 DPB1*1001DQA1*0401 DQB1*0602 DRB1*1401 DPB1*0601 DQA1*0303 DQB1*0503 DRB1*1302DPB1*0501 DQA1*0302 DQB1*0502 DRB1*1301 DPB1*0402 DQA1*0301 DQB1*0501DRB1*1201 DPB1*0401 DQA1*0201 DQB1*0402 DRB1*1104 DPB1*0301 DQA1*0104DQB1*0303 DRB1*1101 DPB1*0201 DQA1*0103 DQB1*0302 DRB1*0801 DPB1*0101DQA1*0102 DQB1*0301 DRB1*0701 DQA1*0101 DQB1*0202 DRB1*0404 DQB1*0201DRB1*0401 DRB1*0301 DRB1*0103 DRB1*0102 DRB1*0101

The most preferred alleles according to the invention are the following:

HLA-A*0201, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*2402, HLA-A*3401,HLA-B*0702, HLA-B*0801, HLA-B*1301, HLA-B*27, HLA-B*4002, HLA-B*5101,HLA-Cw*03, HLA-cW*07

HLA-DRB1*0301, HLA-DRB1*0401, HLA-DRB1*0701, HLA-DRB1*1501,HLA-DRB1*1104, HLA-DRB1*1101, HLA-DRB4*0101

HLA-DQA1*01, HLA-DQA1*02, HLA-DQA1*05

HLA-DQB1*03, HLA-DQB1*04, HLA-DQB1*05, HLA-DQB1*06

HLA-DPA1*01, HLA-DPA1*02

HLA-DPB1*02, HLA-DPB1*04

The invention will now be described by way of example only, withreference to the following specific embodiments.

EXAMPLES Experiment 1 Reactivity of Polypeptides Against InfluenzaAntigens

The purpose of the study was to demonstrate the reactivity of theabove-described influenza polypeptides and their ability to induce aspecific Th1-type cytokine response against naturally processed andpresented influenza proteins in the context of human HLA (HLA A*0201).

As background to the experiments, it is useful to understand that Th1and Th2 responses are defined by the pattern of cytokines produced bythe T helper cells involved in them. That, however, does not mean thatthe remaining lymphocytes (T and B cells) involved in those specificresponses do not also produce cytokines that help drive thecharacteristic pattern of response in which they are involved. In thisway, a Th1-like response is characterised by the production of IFN-γ andIL-2, leading to the stimulation of a CD8⁺ CTL response and anassociated (in mice) IgG2a antibody response. The IFN-γ response can beproduced both by the CD4⁺ T helper 1 cells as well as by the CD8⁺ Tcells that also form part of it. In this case the IFN-γ component of theresponse produced by the CD8⁺ T cells was investigated. That was becausethe experiment was primarily investigating CD8⁺ T cell epitopes and itwas desirable to prove that the response seen was caused by those cells.Since CD8⁺ T cells react to epitopes only on MHC class I molecules,human cells that share with the transgenic mouse only one MHC class Imolecule (i.e. HLA-A*0201) were used. A Th2-like response ischaracterised by the production of IL-4 and IL-10, leading to thestimulation of an IgGE, IgG1 and (in mice) IgG2b antibody response. Bothresponses are antagonistic with IFN-γ and IL-10 downregulating theproduction of each other. All the experiments described below werecarried out in duplicate.

Materials and Methods

Peptides and Recombinant Proteins

All the polypeptides used in this study (i.e. P1: MIA amino acid (aa) 36to 75 (SEQ ID 1); P2: M1B aa 124 to 158 (SEQ ID 2); P3: NPA aa 255 to275 (SEQ ID 3); P4: NPB aa 306 to 326 (SEQ ID 4); P5: PB1 aa 395 to 428(SEQ ID 5); P6: M2 aa 32 to 55 (SEQ ID 6) and NRP: a controlnon-relevant polypeptide) were synthesised by Fmoc chemistry andresuspended in 10% DMSO in PBS.

Cell Lines and Viruses

The T1 and JURKAT cell lines are human lymphoblastoid lines derived fromHLA-A*0201 bearing and non-bearing individuals respectively. T1 wasmaintained in IMDM medium (Invitrogen) whilst JURKAT was maintained inRPMI-1640 medium (Sigma) containing 10 mM HEPES and 1 mM sodiumpyruvate. Both media were supplemented with 50 IU/50 mg/ml ofpenicillin/streptomycin (Sigma) and, as complete medium, 10% FCS. Cellcultures were maintained at 37° C. in a humidified atmosphere of 5% CO2.

Primary splenocytes were maintained in IMDM medium (Invitrogen)supplemented with 0.02 mM β-mercaptoethanol (Sigma), 50 IU/50 mg/ml ofpenicillin/streptomycin (Sigma) and 10% FCS (Sigma) at 37° C. in ahumidified atmosphere of 5% CO2.

Influenza A strains New_Calcdonia/20/99, NYMC/X-147 and Influenza Bstrain Johannesburg/5/99 were obtained from NIBSC as lyophilised stocksand used for the infection of syngeneic (T1) and allogeneic (JURKAT)human cell lines.

Preparation of Target Cells for Cytokine Analysis

Cell cultures in exponential phase were harvested by centrifugation (250g, 5 min) and resuspended at a density of 10⁶ cells/ml in serum-freemedium. Aliquots of the cell suspensions were transfected with a rangeof polypeptide antigens at a concentration of 5 μg per 10⁶ cells usingLipofectin (Invitrogen) according to the manufacturers instructions andincubated in complete medium for 8-10 hours before Mytomicin C (MMC)treatment. Alternatively, aliquots of the cell suspensions were infectedwith a range of live Influenza virus (MOI of 5-10) for one hour, washedtwice in serum free medium and incubated in complete medium for 24 hoursbefore MMC treatment.

For MMC treatment, cells were harvested by centrifugation (250 g, 5 min)and resuspended in serum-free IMDM medium containing 50 μg/ml ofMitomycin C (Sigma). After 45 min incubation at 37° C., the cellsuspensions were washed four times in serum-free IMDM medium (250 g, 5min) and finally resuspended in complete IMDM medium.

Immunizations

Seven to ten week old C57BL/6-Tg(HLA-A2.1)1Enge/J mice (HLA-A*0201transgenic on a C57/BL6 background, Jackson Labs) were immunisedsubcutaneously with a 200 μl dose of the antigen preparation per mouse.In the test group, each dose of the antigen preparation contained 60nmol of an equimolar mixture of all six peptides (10 nmol each) preparedin IFA (Sigma) according to the manufacturers instructions (FLU-vpreparation). In the control group, each dose of the antigen preparationcontained an equivalent dose of the non-relevant polypeptide prepared inIFA (Sigma) according to the manufacturers instructions (NRPpreparation).

On day 14 post-immunisation, all animals received a booster immunisationusing the same doses and route of delivery as used originally. Finally,on day 21 or 22, all animals were culled and their spleens collected.

The immunisation protocol can be represented schematically as shown inFIG. 4.

Statistical Analysis

Statistically significant differences in the IFN-γ response to differentantigens between FLU-v and NRP vaccinated animals were establishedthrough non-parametric Mann-Whitney analysis of the samples. Differenceswere considered statistically significant if the p value was below 0.05.

Cytokine ELISA

Mouse spleens belonging to the same experimental group were pooled,gently pressed through cell strainers and red blood cells removed bytreatment with red cell lysis buffer (nine parts 0.16 M NH₄Cl and onepart of 0.17 M Tris, pH 7.2). Splenocyte suspensions from eachexperimental group were plated in 24-well plates at a density of 4×10⁶cells/well containing a range of polypeptide antigens (5 μg/ml) or,alternatively, MMC treated cell lines (splenocyte to cell (S:C) ratio10:1) either transfected with polypeptide antigens or infected withdifferent live Influenza virus as described above.

After 4 days incubation at 37° C., the supernatant was collected andanalyzed for IFN-γ and IL-4 by a sandwich cytokine ELISA according tothe manufacturers protocol (Pharmingen). The lower detection limits forthe assay were 9.77 μg/ml for IL-4 and 39.06 μg/ml for IFN-γ.

Results

Each individual polypeptide peptide described in this patent application(including P1, P2, P3, P4, P5 and P6 tested in this example) has beendefined as containing T cell epitopes reactive in multiple human HLAmolecules, amongst them HLA-A*0201. The aim of this study is, therefore,to assess the ability of the above described polypeptides to induce aspecific multi-antigen Th1-like immune (i.e. IFN-γ mediated) response aswell as the ability of this response to specifically react to naturallyprocessed and presented Influenza antigens from several non-relatedstrains pathogenic to humans in the context of infected human HLA A*0201bearing cells.

Reactivity of Peptide 1

Upon internal processing of the polypeptide by the antigen presentingcells (APCs) of the transgenic mice, the contained CD8⁺ T cell specificepitopes would be presented in the surface of the APC in associationwith the HLA-A*0201 molecules where they would proceed to activate naiveCD8⁺ T cells and induce a P1 specific Th1-like immune response.

To confirm this, HLA-A*0201 bearing (T1) and non-bearing (JURKAT) humancell lines were intracellularly loaded with P1 by means of a lipidvehicle (Lipofectin, INVITROGEN). Splenocytes from animals immunisedwith the influenza polypeptide preparation (FLU-v) were found to producesignificantly increased levels of IFN-γ compared to splenocytes from NRPimmunised animals when co-cultured with MMC treated HLA-A*0201 bearinghuman cells (T1) transfected with P1, but not when co-cultured withnon-HLA-A*0201 bearing human cells (JURKAT) treated in the same way (seeFIG. 1A, the data for which is presented in Table 1 below).

TABLE 1 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9  2257.5 ±29.8 FLU Peptide 1 (sol) 119.3 ± 7.1 <39 T1-FLU pep 1 (pro)  228.4 ±16.6 55.8 ± 7 Ju-FLU pep 1 (pro) <39   51.2 ± 1.6 Note: “Lys” means thenegative control background upon which all values are calculated. “Sol”means soluble peptide presented to the primary splenocyte population.“Pro” means that the peptide is being presented complexed with thecell's HLA molecules following internal processing and loading of theresulting epitopes on to the MHC molecules. Values represent average ±standard error of the Δ IFN-γ to Lys (pg/ml).

The experiment can be represented schematically as shown in FIG. 5 andFIG. 6.

As the transgenic mice used in these experiments do not bear any otherhuman HLA and the ability of its CD8⁺ T cells to specifically recogniseP1-derived epitopes in the context of other human HLAs which they havenever encountered is low, these results clearly show that the observedIFN-γ response is specifically caused by primed CD8⁺ T cells recognisingP1-derived epitopes in association with HLA-A*0201 molecules.

It is also important to note that no IL-4 response was detected againstthe P1 transfected cells in either FLU-v or NRP immunised animals (datanot shown). Since IL-4 production is antagonistic to IFN-γ productionand hence to the creation of antigen specific CD8⁺ T cell responses, thelack of IL-4 production in both groups clearly shows that immunisationwith FLU-v induces a specific Th1-like response to the P1 component ofthe preparation.

A significantly increased level in IFN-γ production is also observed inthe FLU-v compared to the NRP immunised groups when soluble P1 antigenis simply added to the splenocyte culture (in the absence of T1 orJURKAT cells). However, the overall level of this IFN-γ response islower than that observed when the antigen was presented via theHLA-A*0201 bearing T1 cells. The explanation for this observation isthat P1 was defined on the basis of containing epitopes that areprimarily reactive in the context of human and not mouse HLAs. Thetransgenic mice here used contain a full complement of mouse MHCmolecules in addition to the HLA-A*0201 molecules, hence the soluble P1captured by the APC population present in the primary splenocytecultures can also be processed into the mouse MHC Class I and IIpathways (Peachman K K, Rao M, Alving C R, Palmer D R, Sun W, Rothwell SW. “Human dendritic cells and macrophages exhibit differentintracellular processing pathways for soluble and liposome-encapsulatedantigens.” Immunobiology. 2005; 210(5):321-33), which mediate H-2Drestricted CD8⁺ and CD4⁺ T cell responses respectively. As a result, ifP1 contained multiple murine epitopes, it would be expected that theIFN-γ response to soluble P1 would be equal or greater to that observedfor the case of human cell mediated presentation as a much larger poolof CD4+ and CD8⁺ T cells would be able to react to the stimulus. As thisis not observed and the level of an immune response in vitro isprimarily determined by the availability of antigen, it clearly followsthat the P1-specific CD8⁺ T lymphocytes detected in the T1 co-cultureexperiments would simply be unable to respond at the same level due tothe reduced amount of antigen being presented to them in the correctHLA-A*0201 context.

Reactivity of Peptide 2

Splenocytes from animals immunised with the FLU-v have been found toproduce significantly increased levels of IFN-γ compared to splenocytesfrom NRP immunised animals when co-cultured with MMC treated HLA-A*0201bearing human cells (T1) transfected with P2, but not when co-culturedwith non-HLA-A*0201 bearing human cells (JURKAT) treated in the same way(see FIG. 1B, the data for which is set out in Table 2 below). As it wasthe case for P1, these results clearly show that the observed IFN-γresponse is specifically caused by CD8⁺ T cells recognising P2-derivedepitopes in association with HLA-A*0201 molecules. Similarly, as IL-4production is antagonistic to IFN-γ production and hence to thedevelopment of CD8⁺ T cells, the lack of an IL-4 response against P2transfected cells in either FLU-v or NRP immunised animals (data notshown) clearly shows that FLU-v immunisation induces a P2-specificTh1-like response.

TABLE 2 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9 2257.5 ±29.8  FLU Peptide 1 (sol)  976.9 ± 24.1 468.4 ± 14.7 T1-FLU pep 1 (pro)372.9 ± 6.4 154.5 ± 10.7 Ju-FLU pep 1 (pro) <39 <39 Note: “Lys” meansthe negative control background upon which all values are calculated.“Sol” means soluble peptide presented to the primary splenocytepopulation. “Pro” means that the peptide is being presented complexedwith the cell's HLA molecules following internal processing and loadingof the resulting epitopes on to the MHC molecules. Values representaverage ± standard error of the Δ IFN-γ to Lys (pg/ml).

A significantly increased IFN-γ production was also observed in theFLU-v compared to NRP immunised groups when P2 was simply added to thesplenocyte culture. In contrast to P1, however, the overall level of theIFN-γ response was greater to the soluble antigen than to that presentedby the HLA-A*0201 bearing cells. This observation would indicate that P2harbours not only strong HLA-A*0201 epitopes but also strong mouse(H-2D) epitopes.

Reactivity of Peptides 3, 4 and 5

As was the case for P2, significantly increased IFN-γ production can beobserved between FLU-v and NRP immunised groups when P3, P4 and P5 aresimply added to the culture as well as when they are presented viaHLA-matched transfected human cells lines (T1), but not when they arepresented via HLA-mismatched (JURKAT) human cell lines (see FIGS. 1C, 1Dand 1E, the data for which is set out in Tables 3-5 below). In all threecases, the increment in IFN-γ production is greater when splenocytes areco-cultured with transfected human cells rather than when solubleantigen is simply added to the medium. These results, due to the samearguments developed for the case of P2, indicate that P3, P4 and P5contain a number of strong mouse T cell epitopes in addition to thehuman ones.

TABLE 3 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9 2257.5 ±29.8  FLU Peptide 1 (sol) 1734.1 ± 57.2 268.0 ± 11.0 T1-FLU pep 1 (pro) 587.5 ± 14.9 <39 Ju-FLU pep 1 (pro) 148.5 ± 3.0 146.5 ± 17.6 Note:“Lys” means the negative control background upon which all values arecalculated. “Sol” means soluble peptide presented to the primarysplenocyte population. “Pro” means that the peptide is being presentedcomplexed with the cell's HLA molecules following internal processingand loading of the resulting epitopes on to the MHC molecules. Valuesrepresent average ± standard error of the Δ IFN-γ to Lys (pg/ml).

TABLE 4 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9 2257.5 ±29.8 FLU Peptide 1 (sol) 1170.5 ± 27.8 693.8 ± 5.6 T1-FLU pep 1 (pro) 229.9 ± 35.2  84.6 ± 11.6 Ju-FLU pep 1 (pro) <39 <39 Note: “Lys” meansthe negative control background upon which all values are calculated.“Sol” means soluble peptide presented to the primary splenocytepopulation. “Pro” means that the peptide is being presented complexedwith the cell's HLA molecules following internal processing and loadingof the resulting epitopes on to the MHC molecules. Values representaverage ± standard error of the Δ IFN-γ to Lys (pg/ml).

TABLE 5 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9 2257.5 ±29.8 FLU Peptide 1 (sol) 1067.75 ± 7.3  220.5 ± 6.6 T1-FLU pep 1 (pro) 405.6 ± 11.8 <39 Ju-FLU pep 1 (pro) <39 <39 Note: “Lys” means thenegative control background upon which all values are calculated. “Sol”means soluble peptide presented to the primary splenocyte population.“Pro” means that the peptide is being presented complexed with thecell's HLA molecules following internal processing and loading of theresulting epitopes on to the MHC molecules. Values represent average ±standard error of the Δ IFN-γ to Lys (pg/ml).

Finally, as all three peptides fail to induce the production of IL-4(data not shown), it is clear that the immune response induced byvaccination with the FLU-v preparation induces a Th1-like response toeach of these three polypeptides.

Reactivity of Peptide 6

As was the case for P1, significantly increased IFN-γ production can beobserved between FLU-v and NRP immunised groups when P6 is simply addedto the culture as well as when it is presented via HLA-matchedtransfected human cells lines (T1), but not when it is presented viaHLA-mismatched (JURKAT) human cell lines (see FIG. 1F, the data forwhich is set out in Table 6 below). Again as for P1, the greaterresponse is observed to the soluble antigen, indicating that P6 does notcontain strong H-2D epitopes. As the causes for these observations havealready been explained for the case of P1 they shall not be developedfurther here and one shall refer to that earlier section.

TABLE 6 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9 2257.5 ±29.8 FLU Peptide 1 (sol)  496.2 ± 11.8 105.5 ± 7.0 T1-FLU pep 1 (pro)1210.5 ± 11.5 817.6 ± 8.9 Ju-FLU pep 1 (pro) <39 <39 Note: “Lys” meansthe negative control background upon which all values are calculated.“Sol” means soluble peptide presented to the primary splenocytepopulation. “Pro” means that the peptide is being presented complexedwith the cell's HLA molecules following internal processing and loadingof the resulting epitopes on to the MHC molecules. Values representaverage ± standard error of the Δ IFN-γ to Lys (pg/ml).

The failure of stimulation with P6 to induce any IL-4 production (datanot shown), clearly show that the immune response induced by FLU-vvaccination induces a Th1-like response to P6.

Reactivity of FLU-v to Non-Related Influenza Strains

The experiments described up to this point clearly show thatimmunisation with FLU-v induces a specific CD8⁺ T cell IFN-γ responseagainst each of the six constituent polypeptides. However, as thesepolypeptides were defined as containing reactive CD8⁺ T cell epitopessubject to a low level of sequence variability within the influenzavirus population analyzed, it was also desirable to establish whetherFLU-v vaccinated mice were capable of recognising, and hence inducing aspecific Th1-like immune response, T cell epitopes naturally processedand presented following infection with different non-related strains ofinfluenza. Such analysis provides a clear indication of the potentialefficacy of the FLU-v polypeptide mixture as an influenza vaccine which,by virtue of targeting T cell epitopes of low sequence variabilityacross the human and animal influenza population, would provideprotection against all current strains as well as those which may arisein the future from spontaneous recombination between highly pathogenicanimal strains with current human strains.

For this analysis, primary splenocyte cultures of transgenic animalsimmunised with FLU-v or NRP were co-cultured with several influenzainfected HLA-A*0201 bearing (T1) and non-bearing (JURKAT) human cells.The three influenza strains used for infection (A/New_Calcdonia/20/99,A/NYMC/X-147 and B/Johannesburg/5/99) are all pathogenic to humans andwere obtained from the Influenza WHO repository, based at NIBSC (UK). Asan antigen specific positive control an equimolar soluble preparation ofthe six polypeptides added to the primary splenocyte preparation wasused.

Splenocytes from FLU-v vaccinated animals produced a significantlyhigher level of IFN-γ compared to those of NRP vaccinated animals whenco-cultured with MMC treated influenza infected HLA-A*0201 bearing humancells (T1) transfected, but not when co-cultured with non-HLA-A*0201bearing human cells (JURKAT) treated in the same way (see FIG. 2, thedata for which is set out in Table 7 below). No IL-4 response wasdetected in any of the vaccinated mice against either the solublepolypeptide antigen or the Influenza infected cells (data not shown).These results clearly show that the observed IFN-γ response isspecifically caused by primed CD8⁺ T cells recognising epitopescontained in the FLU-v preparation and which are also naturallyprocessed and presented in association with HLA-A*0201 molecules ininfluenza infected human cells.

TABLE 7 Δ IFN-γ to Lys (pg/ml) FLU-v NRP Con A 2395.6 ± 45.9 2257.5 ±29.8 FLU peptide mix (sol) 1440.2 ± 44.9  678.3 ± 29.2 T1-Flu A/NC/20/992146.4 ± 23.7 1282.1 ± 4.8  Ju-Flu A/NC/20/99 1246.9 ± 48.8 1206.4 ±10.9 T1-Flu A/NYMC/X147 1949.4 ± 37.9  1101 ± 5.9 Ju-Flu A/NYMC/X1471342.3 ± 14.5 1248.6 ± 8.3  T1-Flu B/Johannesburg/5/99 1769.0 ± 33.61196.0 ± 16.2 Ju-Flu B/Johannesburg/5/99 257.6 ± 3.0 257.0 ± 8.3 Note:“Lys” means the negative control background upon which all values arecalculated. “Sol” means soluble peptide presented to the primarysplenocyte population. “Pro” means that the peptide is being presentedcomplexed with the cell's HLA molecules following internal processingand loading of the resulting epitopes on to the MHC molecules. T1 is theHLA-A*0201-bearing human cell line. “Ju” refers to JURKAT which is theHLA-A*0201 non-bearing human cell line. A/NC/20/99 (i.e.A/New_Caledonia/20/99), A/NYMC/X-147 and B/Johannesburg/5/99 are,respectively, the two influenza A and one influenza B strains used forinfection of the human cell lines. Values represent average ± standarderror of the Δ IFN-γ to Lys (pg/ml).

Interestingly, the background production of IFN-γ for all influenzainfected groups was greater than observed when similar analysis werecarried out using purified polypeptide antigen. This observation,however, most likely reflects the inability of MMC treatment to fullyinactivate the virus present in the cell preparation. This, in turn,would result in viable Influenza virus infecting susceptible mouse cellsin the primary splenocyte cultures, thus leading to a primary responsein vitro. This interpretation is sustained by the observation that mostinfluenza virus strains used induced the same level of background IFN-γresponse independently of the human cell line infected and thevaccinated group considered. The only exception to this rule is the muchreduced background IFN-γ production observed in JURKAT cells infectedwith B/Johannesburg/5/99. However, as even in this case IFN-γ productionfor both FLU-v and NRP vaccinated animals is equivalent, it would appearthat the observed difference is caused more by the reducedsusceptibility of JURKAT cells to infection by InfluenzaB/Johannesburg/5/99, than by any cause intrinsically associated to thedifferent vaccination regimes. Whatever the case, this observation, doesnot detract from the clear fact that vaccination with FLU-v leads to thespecific recognition of naturally processed influenza epitopes presentedin association with HLA-A*0201 molecules following infection of humancells with several non-related strains of infectious influenza virus.Therefore, FLU-v constitutes an effective candidate vaccine preparationfor protection against multiple influenza strains, thus obviating theneed for the current yearly re-vaccination protocols.

Experiment 2 Protective Effect of Polypeptides in Mice

The purpose of this study was to demonstrate that low dose immunisationwith the identified Influenza conserved T cell polyepitope peptides(FLU-v) induces protection, mediated by CD8⁺ T cells, against lethalchallenge with the influenza virus.

Materials and Methods

Peptides, Antisera and Virus:

The candidate vaccine preparation (FLU-v) tested in this study iscomposed of several peptides (i.e. P1: MIA amino acid (aa) 36 to 75 (SEQID 1); P2: M1B aa 124 to 158 (SEQ ID 2); P3: NPA aa 255 to 275 (SEQ ID3); P4: NPB aa 306 to 326 (SEQ ID 4); P5: PB1 aa 395 to 428 (SEQ ID 5);P6: M2 aa 32 to 55 (SEQ ID 6)) which were all synthesised by Fmocchemistry and resuspended in DMSO in PBS (the concentration of DMSO inthe final preparation was less than 5%). Lysozyme (Sigma) denatured byboiling was used as the control non relevant preparation (NRP-v).

Purified rat anti-mouse CD8 IgG2a (clone YTS169.4) was obtained from AbDSerotec (UK) whilst the infectious virus Influenza A/PR/8/34 wereobtained from NIBSC as lyophilised standard stock.

Immunizations

On day 1, seven to ten week old C57BL/6-Tg(HLA-A2.1)1Enge/J mice(HLA-A*0201 transgenic on a C57/BL6 background, Jackson Labs) wereimmunised subcutaneously at the base of the tail with a 200 μl dose ofthe antigen preparation emulsified in IFA (Sigma). In the test group(n=14), each dose of the antigen preparation contained 60 nmol of anequimolar mixture of all six peptides (10 nmol each) whilst in thecontrol group (n=14), each dose of the antigen preparation contained anequivalent dose of the non-relevant polypeptide.

On day 15 all animals received a booster immunisation using the samedoses and route of delivery as used originally.

On Day 16 both the test and control groups were split into two equalsubgroups (n=7 each; i.e. Ctrol-1, Ctrol-2, Test-1 and Test-2).

On Day 19, all animals in the Ctrol-1 and Test-1 groups received a 200μl intraperitoneal injection of rat anti-mouse-CD8 sera (100 μg) whilstall animals in the Ctrol-2 and Test-2 groups received an equivalentinjection of unrelated sera.

The following day (Day 20), all groups were challenged intranasallyunder anaesthesia with a large lethal dose (approximately 1.5×10⁷ pfu)of Influenza A/PR/8/34.

On day 22, animals were again intraperitoneally injected with either ratanti-mouse-CD8 or unrelated sera as described above.

From day 20 all animals were monitored daily for symptoms of influenza(e.g. sneezing and pyrexia) as well as weight loss.

All animals still alive on day 27 were culled and the study wasterminated.

Results

In order to assess the efficacy of the FLU-v preparation as a candidateInfluenza vaccine it was desirable to set up a challenge study in NRP-vand FLU-v immunised animals using the Influenza A/PR/8/34 strain.Typically, an intranasal dose of approximately 1.5×10⁷ pfu will killnon-immunised C57BL/6-Tg(HLA-A2.1)1 Enge/J mice on day 4 or 5 afterchallenge (data not shown).

As shown in FIG. 3A, most animals immunised with either the FLU-v orNRP-v peptide preparations, but subject to CD8 depletion, had succumbedto infection by Influenza A/PR/8/34 by day 7 after intranasal challenge(71% vs 100% respectively). In contrast, as shown in FIG. 3B and in theabsence of CD8 depletion, animals immunised with the FLU-v preparationshowed a significant reduction (p<0.05) in their mortality rate comparedto animals immunised with the NRP-v preparation (28% vs 100%).

The results of this study clearly indicate that vaccination with theFLU-v peptide preparation, even at a low level dose of each of itsconstituent active peptides (10 nmol), induces a significant level ofprotection against lethal challenge with Influenza. These peptides, asindicated earlier, where identified in silico primarily by their T cellreactivity within the context of Human HLA Class I. The resultscorroborate the fact that CD8⁺ T cells stimulated by vaccination withthe FLU-v peptide preparation play a significant role in conferringprotection against Influenza infection.

The invention claimed is:
 1. A polypeptide composition, the compositioncomprising an adjuvant and one or more isolated polypeptides, each ofthe one or more isolated polypeptides being from 8 to 50 amino acids inlength, wherein the one or more isolated polypeptides include apolypeptide comprising an amino acid sequence with 85% or more aminoacid sequence identity to SEQ ID NO: 1 or a fragment of SEQ ID NO: 1having 8 or more consecutive amino acids from SEQ ID NO: 1, apolypeptide comprising an amino acid sequence with 85% or more aminoacid sequence identity to SEQ ID NO: 2 or a fragment of SEQ ID NO: 2having 8 or more consecutive amino acids from SEQ ID NO: 2, apolypeptide comprising an amino acid sequence with 85% or more aminoacid sequence identity to SEQ ID NO: 3 or a fragment of SEQ ID NO: 3having 8 or more consecutive amino acids from SEQ ID NO: 3, apolypeptide comprising an amino acid sequence with 85% or more aminoacid sequence identity to SEQ ID NO: 4 or a fragment of SEQ ID NO: 4having 8 or more consecutive amino acids from SEQ ID NO: 4, apolypeptide comprising an amino acid sequence with 85% or more aminoacid sequence identity to SEQ ID NO: 5 or a fragment of SEQ ID NO: 5having 8 or more consecutive amino acids from SEQ ID NO: 5, and apolypeptide comprising an amino acid sequence with 85% or more aminoacid sequence identity to SEQ ID NO: 6 or a fragment of SEQ ID NO: 6having 8 or more consecutive amino acids from SEQ ID NO: 6, wherein, theone or more polypeptides are immunogenic to one or more influenzastrains in a vertebrate expressing a major histocompatibility complex(MHC) allele, and wherein the one or more isolated polypeptides are nota complete influenza virus protein.
 2. The composition according toclaim 1, wherein the one or more isolated polypeptides each comprises acytotoxic T lymphocyte (CTL) epitope.
 3. The composition according toclaim 1, wherein the one or more polypeptides comprise a polypeptidecomprising an amino acid sequence with 95% or more amino acid sequenceidentity to SEQ ID NO: 1 or a fragment of SEQ ID NO: 1 having 9 or moreconsecutive amino acids from SEQ ID NO: 1, a polypeptide comprising anamino acid sequence with 95% or more amino acid sequence identity to SEQID NO: 2 or a fragment of SEQ ID NO: 2 having 9 or more consecutiveamino acids from SEQ ID NO: 2, a polypeptide comprising an amino acidsequence with 95% or more amino acid sequence identity to SEQ ID NO: 3or a fragment of SEQ ID NO: 3 having 9 or more consecutive amino acidsfrom SEQ ID NO: 3, a polypeptide comprising an amino acid sequence with95% or more amino acid sequence identity to SEQ ID NO: 4 or a fragmentof SEQ ID NO: 4 having 9 or more consecutive amino acids from SEQ ID NO:4, a polypeptide comprising an amino acid sequence with 95% or moreamino acid sequence identity to SEQ ID NO: 5 or a fragment of SEQ ID NO:5 having 9 or more consecutive amino acids from SEQ ID NO: 5, and apolypeptide comprising an amino acid sequence with 95% or more aminoacid sequence identity to SEQ ID NO: 6 or a fragment of SEQ ID NO: 6having 9 or more consecutive amino acids from SEQ ID NO:
 6. 4. Thecomposition according to claim 3, wherein the one or more polypeptidescomprise a polypeptide comprising an amino acid sequence with 95% ormore amino acid sequence identity to SEQ ID NO: 1, a polypeptidecomprising an amino acid sequence with 95% or more amino acid sequenceidentity to SEQ ID NO: 2, a polypeptide comprising an amino acidsequence with 95% or more amino acid sequence identity to SEQ ID NO: 3,a polypeptide comprising an amino acid sequence with 95% or more aminoacid sequence identity to SEQ ID NO: 4, a polypeptide comprising anamino acid sequence with 95% or more amino acid sequence identity to SEQID NO: 5, and a polypeptide comprising an amino acid sequence with 95%or more amino acid sequence identity to SEQ ID NO:
 6. 5. The compositionaccording to claim 4, wherein the one or more polypeptides comprise apolypeptide comprising SEQ ID NO: 1, a polypeptide comprising SEQ ID NO:2, a polypeptide comprising SEQ ID NO: 3, a polypeptide comprising SEQID NO: 4, a polypeptide comprising SEQ ID NO: 5, and a polypeptidecomprising SEQ ID NO:
 6. 6. The composition according to claim 5,wherein the one or more polypeptides comprise a polypeptide of SEQ IDNO: 1, a polypeptide of SEQ ID NO: 2, a polypeptide of SEQ ID NO: 3, apolypeptide of SEQ ID NO: 4, a polypeptide of SEQ ID NO: 5, and apolypeptide of SEQ ID NO:
 6. 7. The composition according to claim 1,wherein each of the one or more isolated polypeptides are in an amountof 1 μg to 100 g.
 8. The composition according to claim 1, wherein theadjuvant in incomplete Freund's adjuvant.
 9. The composition accordingto claim 1, which is immunogenic to one influenza virus strains.
 10. Thecomposition according to claim 1, which is immunogenic to a plurality ofinfluenza virus strains.
 11. The composition according to claim 1,wherein the one or more influenza strains includes an influenza Astrain, an influenza B strain, or both an influenza A strain and aninfluenza B strain.
 12. A polypeptide composition, the compositioncomprising an adjuvant and one or more isolated polypeptides, each ofthe one or more isolated polypeptides being from 8 to 50 amino acids inlength, wherein the one or more isolated polypeptides include apolypeptide an amino acid sequence with 85% or more amino acid sequenceidentity to SEQ ID NO: 1 or a fragment of SEQ ID NO: 1 having 8 or moreconsecutive amino acids from SEQ ID NO: 1, a polypeptide comprising anamino acid sequence with 85% or more amino acid sequence identity to SEQID NO: 3 or a fragment of SEQ ID NO: 3 having 8 or more consecutiveamino acids from SEQ ID NO: 3, a polypeptide comprising an amino acidsequence with 85% or more amino acid sequence identity to SEQ ID NO: 4or a fragment of SEQ ID NO: 4 having 8 or more consecutive amino acidsfrom SEQ ID NO: 4, and a polypeptide comprising an amino acid sequencewith 85% or more amino acid sequence identity to SEQ ID NO: 6 or afragment of SEQ ID NO: 61 having 8 or more consecutive amino acids fromSEQ ID NO: 6, wherein, the one or more polypeptides are immunogenic toone or more influenza strains in a vertebrate expressing a majorhistocompatibility complex (MHC) allele, and wherein the one or moreisolated polypeptides are not a complete influenza virus protein. 13.The composition according to claim 12, wherein the one or morepolypeptides comprise a polypeptide comprising an amino acid sequencewith 95% or more amino acid sequence identity to SEQ ID NO: 1 or afragment of SEQ ID NO: 1 having 9 or more consecutive amino acids fromSEQ ID NO: 1, a polypeptide comprising an amino acid sequence with 95%or more amino acid sequence identity to SEQ ID NO: 3 or a fragment ofSEQ ID NO: 3 having 9 or more consecutive amino acids from SEQ ID NO: 3,a polypeptide comprising an amino acid sequence with 95% or more aminoacid sequence identity to SEQ ID NO: 4 or a fragment of SEQ ID NO: 4having 9 or more consecutive amino acids from SEQ ID NO: 4, and apolypeptide comprising an amino acid sequence with 95% or more aminoacid sequence identity to SEQ ID NO:
 6. 14. The composition according toclaim 13, wherein the one or more polypeptides comprise a polypeptidecomprising an amino acid sequence with 95% or more amino acid sequenceidentity to SEQ ID NO: 1, a polypeptide comprising an amino acidsequence with 95% or more amino acid sequence identity to SEQ ID NO: 3,a polypeptide comprising an amino acid sequence with 95% or more aminoacid sequence identity to SEQ ID NO: 4, and a polypeptide comprising anamino acid sequence with 95% or more amino acid sequence identity to SEQID NO:
 6. 15. The composition according to claim 14, wherein the one ormore polypeptides comprise a polypeptide comprising SEQ ID NO: 1, apolypeptide comprising SEQ ID NO: 3, a polypeptide comprising SEQ ID NO:4, and a polypeptide comprising SEQ ID NO:
 6. 16. The compositionaccording to claim 15, wherein the one or more polypeptides comprise apolypeptide of SEQ ID NO: 1, a polypeptide of SEQ ID NO: 3, apolypeptide of SEQ ID NO: 4, and a polypeptide of SEQ ID NO:
 6. 17. Thecomposition according to claim 12, further comprising a polypeptidecomprising an amino acid sequence with 85% or more amino acid sequenceidentity to SEQ ID NO: 2 or a fragment of SEQ ID NO: 2 having 8 or moreconsecutive amino acids from SEQ ID NO: 2, and a polypeptide comprisingan amino acid sequence with 85% or more amino acid sequence identity toSEQ ID NO: 5 or a fragment of SEQ ID NO: 5 having 8 or more consecutiveamino acids from SEQ ID NO:
 5. 18. The composition according to claim12, further comprising a polypeptide comprising an amino acid sequencewith 95% or more amino acid sequence identity to SEQ ID NO: 2 or afragment of SEQ ID NO: 2 having 9 or more consecutive amino acids fromSEQ ID NO: 2, and a polypeptide comprising an amino acid sequence with95% or more amino acid sequence identity to SEQ ID NO: 5 or a fragmentof SEQ ID NO: 5 having 9 or more consecutive amino acids from SEQ ID NO:5.
 19. The composition according to claim 12, further comprising apolypeptide comprising an amino acid sequence with 95% or more aminoacid sequence identity to SEQ ID NO: 2, and a polypeptide comprising anamino acid sequence with 95% or more amino acid sequence identity to SEQID NO:
 5. 20. The composition according to claim 12, further comprisinga polypeptide comprising SEQ ID NO: 2, and a polypeptide comprising SEQID NO:
 5. 21. The composition according to claim 12, further comprisinga polypeptide of SEQ ID NO: 2, and a polypeptide of SEQ ID NO:
 5. 22.The composition according to claim 12, wherein each of the one or moreisolated polypeptides are in an amount of 1 μg to 100 g.
 23. Thecomposition according to claim 12, wherein the adjuvant in incompleteFreund's adjuvant.
 24. The composition according to claim 12, which isimmunogenic to one influenza virus strains.
 25. The compositionaccording to claim 12, which is immunogenic to a plurality of influenzavirus strains.
 26. The composition according to claim 12, wherein theone or more influenza strains includes an influenza A strain, aninfluenza B strain, or both an influenza A strain and an influenza Bstrain.